{"schema":"melek-hemp-science/cyp-interaction-matrix/1","generatedFrom":"knowledge/hemp-science/cyp450.mjs","updated":"2026-09-27","absenceIsNotSafety":true,"statement":"A substance or pair absent from this matrix was NOT checked and is NOT thereby safe. This is a curated mechanism table from primary literature and regulatory reference works, not a comprehensive interaction database, and it is not a substitute for a clinician or pharmacist.","potencyDefinitions":{"strong":"causes a >=5-fold increase in AUC of a sensitive substrate (FDA classification)","moderate":"causes a >=2-fold but <5-fold increase in AUC","weak":"causes a >=1.25-fold but <2-fold increase in AUC","variable":"reported effect differs substantially between studies or preparations","unclear":"direction known, magnitude not established in humans"},"enzymes":[{"id":"cyp3a4","name":"CYP3A4","page":"/science/cyp450/cyp3a4","substrates":[{"name":"Simvastatin","nti":false,"note":"Sensitive index substrate; grapefruit juice raised AUC roughly sixteen-fold. Accumulation causes myopathy and rhabdomyolysis.","cites":["lilja1998","bailey2013","flockhart"]},{"name":"Lovastatin","nti":false,"note":"Same lactone chemistry and vulnerability as simvastatin.","cites":["flockhart","fdaTable"]},{"name":"Atorvastatin","nti":false,"note":"CYP3A4 substrate with a lower fractional contribution than simvastatin, so a smaller interaction.","cites":["flockhart","fdaTable"]},{"name":"Ciclosporin","nti":true,"note":"Inhibition gives nephrotoxicity; induction gives graft rejection. Also a P-glycoprotein substrate.","cites":["ruschitzka2000","fdaTable","flockhart"]},{"name":"Tacrolimus","nti":true,"note":"Very narrow window; CYP3A5 expressor status also changes dose requirement.","cites":["kuehl2001","fdaTable"]},{"name":"Midazolam","nti":false,"note":"The standard CYP3A4 probe substrate; oral bioavailability limited by gut and hepatic CYP3A.","cites":["thummel1996","flockhart","fdaTable"]},{"name":"Triazolam","nti":false,"note":"Accumulation presents as prolonged sedation and psychomotor impairment.","cites":["flockhart","fdaTable"]},{"name":"Alprazolam","nti":false,"note":"CYP3A4 substrate, unlike the glucuronidated benzodiazepines lorazepam, oxazepam and temazepam.","cites":["flockhart","fdaTable"]},{"name":"Felodipine","nti":false,"note":"The drug in which the grapefruit interaction was discovered by accident.","cites":["bailey1991","lown1997","bailey2013"]},{"name":"Nifedipine","nti":false,"note":"Dihydropyridine; accumulation gives hypotension and reflex tachycardia.","cites":["bailey1991","flockhart"]},{"name":"Amiodarone","nti":true,"note":"Substrate and inhibitor at once, with a half-life measured in weeks.","cites":["flockhart","fdaTable","crediblemeds"]},{"name":"Quinidine","nti":true,"note":"A CYP3A4 substrate that is also the reference strong CYP2D6 inhibitor.","cites":["flockhart","fdaTable"]},{"name":"Ergotamine","nti":true,"note":"Accumulation causes ergotism and peripheral ischaemia; the classic macrolide contraindication.","cites":["flockhart","fdaTable"]},{"name":"Ritonavir and other HIV protease inhibitors","nti":true,"note":"Substrates and potent inhibitors; the interaction is used deliberately as a booster.","cites":["piscitelli2000","fdaTable"]},{"name":"Apixaban","nti":false,"note":"CYP3A4 and P-glycoprotein substrate; dual inhibition raises bleeding risk.","cites":["fdaTable","flockhart"]},{"name":"Rivaroxaban","nti":false,"note":"CYP3A4 and P-glycoprotein substrate.","cites":["fdaTable","flockhart"]},{"name":"Kinase inhibitors (imatinib, ibrutinib and others)","nti":false,"note":"Oral, high first pass, narrow tolerability; labels frequently carry explicit CYP3A4 dose adjustments.","cites":["fdaTable"]},{"name":"Ethinylestradiol and progestin contraceptives","nti":false,"note":"Induction causes breakthrough bleeding and contraceptive failure.","cites":["henderson2002","fdaTable"]},{"name":"Buspirone","nti":false,"note":"Textbook CYP3A4 victim; grapefruit raises exposure severalfold.","cites":["bailey2013","flockhart"]},{"name":"Clobazam","nti":false,"note":"Parent drug via CYP3A4; the active N-desmethyl metabolite is cleared by CYP2C19.","cites":["geffrey2015","morrison2019"]},{"name":"Δ9-THC","nti":false,"note":"Metabolised by CYP3A4 alongside CYP2C9, which is dominant for 11-hydroxylation.","cites":["watanabe2007","sachseseeboth2009","stout2014"]},{"name":"Cannabidiol","nti":false,"note":"CYP3A4 and CYP2C19 are the principal oxidative routes, followed by extensive glucuronidation.","cites":["jiang2011","stout2014"]},{"name":"Kavalactones","nti":false,"note":"Kava constituents are handled by CYP enzymes including CYP3A4 — the basis of the potentiation claims in the operator corpus.","cites":["mathews2002","zou2002","kavaDatasheet2026"]}],"inhibitors":[{"name":"Ketoconazole","kind":"drug","role":"inhibits","potency":"strong","mechanismBased":false,"note":"The historical reference strong inhibitor; azole nitrogen coordinates the haem iron.","cites":[{"key":"fdaTable","text":"U.S. Food and Drug Administration (2023) Drug Development and Drug Interactions: Table of Substrates, Inhibitors and Inducers FDA","url":"https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-drug-interactions-table-substrates-inhibitors-and-inducers"},{"key":"flockhart","text":"Flockhart DA, Thacker D, McDonald C, Desta Z (2021) The Flockhart Cytochrome P450 Drug-Drug Interaction Table Division of Clinical Pharmacology, Indiana University School of Medicine","url":"https://drug-interactions.medicine.iu.edu"}]},{"name":"Itraconazole","kind":"drug","role":"inhibits","potency":"strong","mechanismBased":false,"note":"Also a substrate, so the interaction can run both ways.","cites":[{"key":"fdaTable","text":"U.S. Food and Drug Administration (2023) Drug Development and Drug Interactions: Table of Substrates, Inhibitors and Inducers FDA","url":"https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-drug-interactions-table-substrates-inhibitors-and-inducers"}]},{"name":"Voriconazole","kind":"drug","role":"inhibits","potency":"strong","mechanismBased":false,"note":"Substrate and inhibitor; also a CYP2C19 substrate and inhibitor.","cites":[{"key":"fdaTable","text":"U.S. Food and Drug Administration (2023) Drug Development and Drug Interactions: Table of Substrates, Inhibitors and Inducers FDA","url":"https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-drug-interactions-table-substrates-inhibitors-and-inducers"},{"key":"flockhart","text":"Flockhart DA, Thacker D, McDonald C, Desta Z (2021) The Flockhart Cytochrome P450 Drug-Drug Interaction Table Division of Clinical Pharmacology, Indiana University School of Medicine","url":"https://drug-interactions.medicine.iu.edu"}]},{"name":"Posaconazole","kind":"drug","role":"inhibits","potency":"strong","mechanismBased":false,"note":"Strong CYP3A4 inhibitor used in prophylaxis, so exposure is prolonged.","cites":[{"key":"fdaTable","text":"U.S. Food and Drug Administration (2023) Drug Development and Drug Interactions: Table of Substrates, Inhibitors and Inducers FDA","url":"https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-drug-interactions-table-substrates-inhibitors-and-inducers"}]},{"name":"Ritonavir","kind":"drug","role":"inhibits","potency":"strong","mechanismBased":true,"note":"Mechanism-based; used deliberately as a pharmacokinetic booster.","cites":[{"key":"fdaTable","text":"U.S. Food and Drug Administration (2023) Drug Development and Drug Interactions: Table of Substrates, Inhibitors and Inducers FDA","url":"https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-drug-interactions-table-substrates-inhibitors-and-inducers"},{"key":"orr2012","text":"Orr STM, Ripp SL, Ballard TE, et al. (2012) Mechanism-based inactivation (MBI) of cytochrome P450 enzymes: structure-activity relationships and discovery strategies to mitigate drug-drug interaction risks Journal of Medicinal Chemistry","url":"https://doi.org/10.1021/jm300065h"}]},{"name":"Cobicistat","kind":"drug","role":"inhibits","potency":"strong","mechanismBased":true,"note":"A booster with no antiviral activity of its own — inhibition is its only purpose.","cites":[{"key":"fdaTable","text":"U.S. Food and Drug Administration (2023) Drug Development and Drug Interactions: Table of Substrates, Inhibitors and Inducers FDA","url":"https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-drug-interactions-table-substrates-inhibitors-and-inducers"}]},{"name":"Clarithromycin","kind":"drug","role":"inhibits","potency":"strong","mechanismBased":true,"note":"Mechanism-based via a nitrosoalkane-iron complex; the classic ergot and statin contraindication.","cites":[{"key":"fdaTable","text":"U.S. Food and Drug Administration (2023) Drug Development and Drug Interactions: Table of Substrates, Inhibitors and Inducers FDA","url":"https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-drug-interactions-table-substrates-inhibitors-and-inducers"},{"key":"orr2012","text":"Orr STM, Ripp SL, Ballard TE, et al. (2012) Mechanism-based inactivation (MBI) of cytochrome P450 enzymes: structure-activity relationships and discovery strategies to mitigate drug-drug interaction risks Journal of Medicinal Chemistry","url":"https://doi.org/10.1021/jm300065h"}]},{"name":"Telithromycin","kind":"drug","role":"inhibits","potency":"strong","mechanismBased":true,"note":"Same mechanism-based macrolide chemistry.","cites":[{"key":"fdaTable","text":"U.S. Food and Drug Administration (2023) Drug Development and Drug Interactions: Table of Substrates, Inhibitors and Inducers FDA","url":"https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-drug-interactions-table-substrates-inhibitors-and-inducers"}]},{"name":"Erythromycin","kind":"drug","role":"inhibits","potency":"moderate","mechanismBased":true,"note":"Same chemistry as clarithromycin at lower potency.","cites":[{"key":"fdaTable","text":"U.S. Food and Drug Administration (2023) Drug Development and Drug Interactions: Table of Substrates, Inhibitors and Inducers FDA","url":"https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-drug-interactions-table-substrates-inhibitors-and-inducers"},{"key":"orr2012","text":"Orr STM, Ripp SL, Ballard TE, et al. (2012) Mechanism-based inactivation (MBI) of cytochrome P450 enzymes: structure-activity relationships and discovery strategies to mitigate drug-drug interaction risks Journal of Medicinal Chemistry","url":"https://doi.org/10.1021/jm300065h"}]},{"name":"Azithromycin","kind":"drug","role":"inhibits","potency":"weak","mechanismBased":false,"note":"Named explicitly because it is the macrolide that largely escapes this problem.","cites":[{"key":"fdaTable","text":"U.S. Food and Drug Administration (2023) Drug Development and Drug Interactions: Table of Substrates, Inhibitors and Inducers FDA","url":"https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-drug-interactions-table-substrates-inhibitors-and-inducers"},{"key":"flockhart","text":"Flockhart DA, Thacker D, McDonald C, Desta Z (2021) The Flockhart Cytochrome P450 Drug-Drug Interaction Table Division of Clinical Pharmacology, Indiana University School of Medicine","url":"https://drug-interactions.medicine.iu.edu"}]},{"name":"Diltiazem","kind":"drug","role":"inhibits","potency":"moderate","mechanismBased":false,"note":"Also inhibits P-glycoprotein, compounding the effect on shared substrates.","cites":[{"key":"fdaTable","text":"U.S. Food and Drug Administration (2023) Drug Development and Drug Interactions: Table of Substrates, Inhibitors and Inducers FDA","url":"https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-drug-interactions-table-substrates-inhibitors-and-inducers"},{"key":"flockhart","text":"Flockhart DA, Thacker D, McDonald C, Desta Z (2021) The Flockhart Cytochrome P450 Drug-Drug Interaction Table Division of Clinical Pharmacology, Indiana University School of Medicine","url":"https://drug-interactions.medicine.iu.edu"}]},{"name":"Verapamil","kind":"drug","role":"inhibits","potency":"moderate","mechanismBased":false,"note":"Also the classical P-glycoprotein inhibitor.","cites":[{"key":"fdaTable","text":"U.S. Food and Drug Administration (2023) Drug Development and Drug Interactions: Table of Substrates, Inhibitors and Inducers FDA","url":"https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-drug-interactions-table-substrates-inhibitors-and-inducers"},{"key":"wandel2002","text":"Wandel C, Kim RB, Kajiji S, Guengerich FP, Wilkinson GR, Wood AJJ (2002) P-glycoprotein and cytochrome P-450 3A inhibition: dissociation of inhibitory potencies Cancer Research [identifier unverified]","url":""}]},{"name":"Fluconazole","kind":"drug","role":"inhibits","potency":"moderate","mechanismBased":false,"note":"Dose dependent; a stronger CYP2C9 and CYP2C19 inhibitor than a CYP3A4 one.","cites":[{"key":"fdaTable","text":"U.S. Food and Drug Administration (2023) Drug Development and Drug Interactions: Table of Substrates, Inhibitors and Inducers FDA","url":"https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-drug-interactions-table-substrates-inhibitors-and-inducers"},{"key":"holbrook2005","text":"Holbrook AM, Pereira JA, Labiris R, et al. (2005) Systematic Overview of Warfarin and Its Drug and Food Interactions Archives of Internal Medicine","url":"https://doi.org/10.1001/archinte.165.10.1095"}]},{"name":"Nefazodone","kind":"drug","role":"inhibits","potency":"strong","mechanismBased":false,"note":"Withdrawn in several markets; retained as a reference case.","cites":[{"key":"fdaTable","text":"U.S. Food and Drug Administration (2023) Drug Development and Drug Interactions: Table of Substrates, Inhibitors and Inducers FDA","url":"https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-drug-interactions-table-substrates-inhibitors-and-inducers"}]},{"name":"Cimetidine","kind":"drug","role":"inhibits","potency":"weak","mechanismBased":false,"note":"Broad weak inhibition; famotidine and ranitidine do not share it.","cites":[{"key":"flockhart","text":"Flockhart DA, Thacker D, McDonald C, Desta Z (2021) The Flockhart Cytochrome P450 Drug-Drug Interaction Table Division of Clinical Pharmacology, Indiana University School of Medicine","url":"https://drug-interactions.medicine.iu.edu"}]},{"name":"Amiodarone","kind":"drug","role":"inhibits","potency":"moderate","mechanismBased":false,"note":"Very long half-life, so the interaction persists for weeks after stopping.","cites":[{"key":"flockhart","text":"Flockhart DA, Thacker D, McDonald C, Desta Z (2021) The Flockhart Cytochrome P450 Drug-Drug Interaction Table Division of Clinical Pharmacology, Indiana University School of Medicine","url":"https://drug-interactions.medicine.iu.edu"},{"key":"fdaTable","text":"U.S. Food and Drug Administration (2023) Drug Development and Drug Interactions: Table of Substrates, Inhibitors and Inducers FDA","url":"https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-drug-interactions-table-substrates-inhibitors-and-inducers"}]},{"name":"Grapefruit juice","kind":"botanical","role":"inhibits","potency":"strong","mechanismBased":true,"note":"Mechanism-based inactivation of INTESTINAL CYP3A4 by the furanocoumarins bergamottin and 6',7'-dihydroxybergamottin. One 200-300 mL glass suffices; CYP3A recovery takes roughly 24-72 hours, so separating juice from dose within the day does not avoid it. A furanocoumarin-free juice does not reproduce the effect.","cites":[{"key":"bailey2013","text":"Bailey DG, Dresser G, Arnold JMO (2013) Grapefruit–medication interactions: Forbidden fruit or avoidable consequences? CMAJ (published online 2012-11-26)","url":"https://doi.org/10.1503/cmaj.120951"},{"key":"paine2006","text":"Paine MF, Widmer WW, Hart HL, et al. (2006) A furanocoumarin-free grapefruit juice establishes furanocoumarins as the mediators of the grapefruit juice-felodipine interaction The American Journal of Clinical Nutrition","url":"https://doi.org/10.1093/ajcn/83.5.1097"},{"key":"edwards1996","text":"Edwards DJ, Bellevue FH 3rd, Woster PM (1996) Identification of 6',7'-dihydroxybergamottin, a cytochrome P450 inhibitor, in grapefruit juice Drug Metabolism and Disposition","url":"https://doi.org/10.1016/s0090-9556(25)08464-8"},{"key":"lown1997","text":"Lown KS, Bailey DG, Fontana RJ, et al. (1997) Grapefruit juice increases felodipine oral availability in humans by decreasing intestinal CYP3A protein expression Journal of Clinical Investigation","url":"https://doi.org/10.1172/JCI119439"},{"key":"lundahl1995","text":"Lundahl J, Regårdh CG, Edgar B, Johnsson G (1995) Relationship between time of intake of grapefruit juice and its effect on pharmacokinetics and pharmacodynamics of felodipine in healthy subjects European Journal of Clinical Pharmacology","url":"https://doi.org/10.1007/BF00192360"},{"key":"greenblatt2003","text":"Greenblatt DJ, von Moltke LL, Harmatz JS, et al. (2003) Time course of recovery of cytochrome p450 3A function after single doses of grapefruit juice Clinical Pharmacology & Therapeutics","url":"https://doi.org/10.1016/S0009-9236(03)00118-8"}]},{"name":"Seville (sour) orange, pomelo, tangelo","kind":"food","role":"inhibits","potency":"moderate","mechanismBased":true,"note":"Same furanocoumarin chemistry as grapefruit. Sweet orange and ordinary orange juice do NOT carry it.","cites":[{"key":"bailey2013","text":"Bailey DG, Dresser G, Arnold JMO (2013) Grapefruit–medication interactions: Forbidden fruit or avoidable consequences? CMAJ (published online 2012-11-26)","url":"https://doi.org/10.1503/cmaj.120951"},{"key":"paine2006","text":"Paine MF, Widmer WW, Hart HL, et al. (2006) A furanocoumarin-free grapefruit juice establishes furanocoumarins as the mediators of the grapefruit juice-felodipine interaction The American Journal of Clinical Nutrition","url":"https://doi.org/10.1093/ajcn/83.5.1097"}]},{"name":"Piperine (black pepper, long pepper)","kind":"botanical","role":"inhibits","potency":"moderate","mechanismBased":false,"note":"Characterised as a relatively SELECTIVE CYP3A4 inhibitor among common spice constituents, and also a P-glycoprotein inhibitor. The pairing is why 20 mg piperine raised curcumin bioavailability roughly twentyfold in human volunteers, and one small clinical study reported a roughly 47 percent rise in steady-state carbamazepine exposure from 20 mg piperine daily.","cites":[{"key":"bhardwaj2002","text":"Bhardwaj RK, Glaeser H, Becquemont L, Klotz U, Gupta SK, Fromm MF (2002) Piperine, a Major Constituent of Black Pepper, Inhibits Human P-glycoprotein and CYP3A4 The Journal of Pharmacology and Experimental Therapeutics","url":"https://doi.org/10.1124/jpet.102.034728"},{"key":"volak2008","text":"Volak LP, Ghirmai S, Cashman JR, Court MH (2008) Curcuminoids Inhibit Multiple Human Cytochromes P450, UDP-Glucuronosyltransferase, and Sulfotransferase Enzymes, whereas Piperine is a Relatively Selective CYP3A4 Inhibitor Drug Metabolism and Disposition","url":"https://doi.org/10.1124/dmd.108.020552"},{"key":"shoba1998","text":"Shoba G, Joy D, Joseph T, Majeed M, Rajendran R, Srinivas PSSR (1998) Influence of Piperine on the Pharmacokinetics of Curcumin in Animals and Human Volunteers Planta Medica","url":"https://doi.org/10.1055/s-2006-957450"},{"key":"pattanaik2009","text":"Pattanaik S, Hota D, Prabhakar S, Kharbanda P, Pandhi P (2009) Effect of piperine on the steady-state pharmacokinetics of carbamazepine in patients with epilepsy Phytotherapy Research [identifier unverified]","url":""}]},{"name":"Curcumin and other curcuminoids (turmeric)","kind":"botanical","role":"inhibits","potency":"moderate","mechanismBased":false,"note":"Inhibits multiple CYPs plus UGT and SULT. Human relevance limited by low oral bioavailability unless co-formulated with piperine or a lipid carrier.","cites":[{"key":"volak2008","text":"Volak LP, Ghirmai S, Cashman JR, Court MH (2008) Curcuminoids Inhibit Multiple Human Cytochromes P450, UDP-Glucuronosyltransferase, and Sulfotransferase Enzymes, whereas Piperine is a Relatively Selective CYP3A4 Inhibitor Drug Metabolism and Disposition","url":"https://doi.org/10.1124/dmd.108.020552"},{"key":"bahramsoltani2017","text":"Bahramsoltani R, Rahimi R, Farzaei MH (2017) Pharmacokinetic interactions of curcuminoids with conventional drugs: A review Journal of Ethnopharmacology","url":"https://doi.org/10.1016/j.jep.2017.07.022"}]},{"name":"Kavalactones (kava)","kind":"botanical","role":"inhibits","potency":"variable","mechanismBased":false,"note":"Methysticin and dihydromethysticin are potent inhibitors in vitro, and the methylenedioxyphenyl motif is associated with mechanism-based inactivation. An in-vivo human probe study did NOT find a significant CYP3A4/5 change. Unresolved.","cites":[{"key":"mathews2002","text":"Mathews JM, Etheridge AS, Black SR (2002) Inhibition of human cytochrome P450 activities by kava extract and kavalactones Drug Metabolism and Disposition","url":"https://doi.org/10.1124/dmd.30.11.1153"},{"key":"zou2002","text":"Zou L, Harkey MR, Henderson GL (2002) Effects of herbal components on cDNA-expressed cytochrome P450 enzyme catalytic activity Life Sciences","url":"https://doi.org/10.1016/s0024-3205(02)01913-6"},{"key":"gurley2005","text":"Gurley BJ, Gardner SF, Hubbard MA, et al. (2005) In vivo effects of goldenseal, kava kava, black cohosh, and valerian on human cytochrome P450 1A2, 2D6, 2E1, and 3A4/5 phenotypes Clinical Pharmacology & Therapeutics","url":"https://doi.org/10.1016/j.clpt.2005.01.009"},{"key":"kavaDatasheet2026","text":"Van Kush Family Research Institute (Temple Pharmacopoeia Project) (2026) Kava Potentiators Datasheet, reconstructed from the 2020 KavaForums potentiators thread Operator corpus, MELEK knowledge base [identifier unverified]","url":""}]},{"name":"Goldenseal (berberine, hydrastine)","kind":"botanical","role":"inhibits","potency":"moderate","mechanismBased":false,"note":"One of the few botanicals with an in-vivo human probe study showing significant CYP3A4/5 inhibition.","cites":[{"key":"gurley2005","text":"Gurley BJ, Gardner SF, Hubbard MA, et al. (2005) In vivo effects of goldenseal, kava kava, black cohosh, and valerian on human cytochrome P450 1A2, 2D6, 2E1, and 3A4/5 phenotypes Clinical Pharmacology & Therapeutics","url":"https://doi.org/10.1016/j.clpt.2005.01.009"}]},{"name":"Cannabidiol (CBD)","kind":"botanical","role":"inhibits","potency":"moderate","mechanismBased":false,"note":"Inhibits CYP3A isoforms in vitro, with the resorcinol phenolic hydroxyls implicated; also a CYP3A4 substrate, so it competes as well as inhibits.","cites":[{"key":"yamaoriSeries","text":"Yamaori S, Ebisawa J, Okushima Y, Kushihara M, Okamoto Y, Yamamoto I, Watanabe K, et al. (2011) Series of in-vitro studies characterising cannabidiol, cannabinol and Δ9-THC as isoform-selective inhibitors of human CYP1, CYP2C19, CYP2D6 and CYP3A enzymes (published 2010-2012 across Life Sciences, Biochemical Pharmacology and Drug Metabolism and Disposition) Life Sciences / Biochemical Pharmacology / Drug Metabolism and Disposition [identifier unverified]","url":""},{"key":"jiang2011","text":"Jiang R, Yamaori S, Takeda S, Yamamoto I, Watanabe K (2011) Identification of cytochrome P450 enzymes responsible for metabolism of cannabidiol by human liver microsomes Life Sciences","url":"https://doi.org/10.1016/j.lfs.2011.05.018"},{"key":"stout2014","text":"Stout SM, Cimino NM (2014) Exogenous cannabinoids as substrates, inhibitors, and inducers of human drug metabolizing enzymes: a systematic review Drug Metabolism Reviews","url":"https://doi.org/10.3109/03602532.2013.849268"}]},{"name":"Δ9-THC","kind":"botanical","role":"inhibits","potency":"weak","mechanismBased":false,"note":"Predominantly a substrate at this isoform; weak inhibitory activity reported in vitro, including from its metabolites.","cites":[{"key":"yamaoriSeries","text":"Yamaori S, Ebisawa J, Okushima Y, Kushihara M, Okamoto Y, Yamamoto I, Watanabe K, et al. (2011) Series of in-vitro studies characterising cannabidiol, cannabinol and Δ9-THC as isoform-selective inhibitors of human CYP1, CYP2C19, CYP2D6 and CYP3A enzymes (published 2010-2012 across Life Sciences, Biochemical Pharmacology and Drug Metabolism and Disposition) Life Sciences / Biochemical Pharmacology / Drug Metabolism and Disposition [identifier unverified]","url":""},{"key":"nasrin2021","text":"Nasrin S, Watson CJW, Perez-Paramo YX, Lazarus P (2021) Cannabinoid metabolites as inhibitors of major hepatic CYP450 enzymes, with implications for cannabis-drug interactions Drug Metabolism and Disposition","url":"https://doi.org/10.1124/dmd.121.000442"},{"key":"stout2014","text":"Stout SM, Cimino NM (2014) Exogenous cannabinoids as substrates, inhibitors, and inducers of human drug metabolizing enzymes: a systematic review Drug Metabolism Reviews","url":"https://doi.org/10.3109/03602532.2013.849268"}]},{"name":"Raw crushed garlic (allicin, allyl sulfides)","kind":"botanical","role":"inhibits","potency":"unclear","mechanismBased":false,"note":"Claimed in the operator corpus and forum material. Human pharmacokinetic data on garlic are inconsistent; it is better documented at CYP2E1 and with saquinavir than at CYP3A4.","cites":[{"key":"kavaDatasheet2026","text":"Van Kush Family Research Institute (Temple Pharmacopoeia Project) (2026) Kava Potentiators Datasheet, reconstructed from the 2020 KavaForums potentiators thread Operator corpus, MELEK knowledge base [identifier unverified]","url":""},{"key":"gurley2005","text":"Gurley BJ, Gardner SF, Hubbard MA, et al. (2005) In vivo effects of goldenseal, kava kava, black cohosh, and valerian on human cytochrome P450 1A2, 2D6, 2E1, and 3A4/5 phenotypes Clinical Pharmacology & Therapeutics","url":"https://doi.org/10.1016/j.clpt.2005.01.009"}]},{"name":"Black seed (Nigella sativa, thymoquinone)","kind":"botanical","role":"inhibits","potency":"unclear","mechanismBased":false,"note":"Operator-corpus entry. In-vitro and animal signals only; human magnitude unestablished.","cites":[{"key":"kavaDatasheet2026","text":"Van Kush Family Research Institute (Temple Pharmacopoeia Project) (2026) Kava Potentiators Datasheet, reconstructed from the 2020 KavaForums potentiators thread Operator corpus, MELEK knowledge base [identifier unverified]","url":""}]},{"name":"Peppermint oil","kind":"botanical","role":"inhibits","potency":"weak","mechanismBased":false,"note":"In-vitro signal without established human relevance at dietary exposure.","cites":[{"key":"flockhart","text":"Flockhart DA, Thacker D, McDonald C, Desta Z (2021) The Flockhart Cytochrome P450 Drug-Drug Interaction Table Division of Clinical Pharmacology, Indiana University School of Medicine","url":"https://drug-interactions.medicine.iu.edu"}]},{"name":"Watercress","kind":"food","role":"inhibits","potency":"weak","mechanismBased":false,"note":"Better documented at CYP2E1; the CYP3A4 signal is weak.","cites":[{"key":"kall1996","text":"Kall MA, Vang O, Clausen J (1996) Effects of dietary broccoli on human in vivo drug metabolizing enzymes: evaluation of caffeine, oestrone and chlorzoxazone metabolism Carcinogenesis","url":"https://doi.org/10.1093/carcin/17.4.793"},{"key":"gurley2005","text":"Gurley BJ, Gardner SF, Hubbard MA, et al. (2005) In vivo effects of goldenseal, kava kava, black cohosh, and valerian on human cytochrome P450 1A2, 2D6, 2E1, and 3A4/5 phenotypes Clinical Pharmacology & Therapeutics","url":"https://doi.org/10.1016/j.clpt.2005.01.009"}]},{"name":"Resveratrol","kind":"botanical","role":"inhibits","potency":"weak","mechanismBased":false,"note":"In-vitro inhibition; human magnitude at supplement doses unestablished.","cites":[{"key":"flockhart","text":"Flockhart DA, Thacker D, McDonald C, Desta Z (2021) The Flockhart Cytochrome P450 Drug-Drug Interaction Table Division of Clinical Pharmacology, Indiana University School of Medicine","url":"https://drug-interactions.medicine.iu.edu"}]},{"name":"Quercetin","kind":"botanical","role":"inhibits","potency":"weak","mechanismBased":false,"note":"In-vitro flavonoid inhibition; also a weak P-glycoprotein inhibitor.","cites":[{"key":"flockhart","text":"Flockhart DA, Thacker D, McDonald C, Desta Z (2021) The Flockhart Cytochrome P450 Drug-Drug Interaction Table Division of Clinical Pharmacology, Indiana University School of Medicine","url":"https://drug-interactions.medicine.iu.edu"}]}],"inducers":[{"name":"Rifampicin (rifampin)","kind":"drug","role":"induces","potency":"strong","mechanismBased":false,"note":"The reference PXR-mediated strong inducer; induces P-glycoprotein and UGT as well.","cites":[{"key":"fdaTable","text":"U.S. Food and Drug Administration (2023) Drug Development and Drug Interactions: Table of Substrates, Inhibitors and Inducers FDA","url":"https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-drug-interactions-table-substrates-inhibitors-and-inducers"},{"key":"greiner1999","text":"Greiner B, Eichelbaum M, Fritz P, et al. (1999) The role of intestinal P-glycoprotein in the interaction of digoxin and rifampin Journal of Clinical Investigation","url":"https://doi.org/10.1172/jci6663"}]},{"name":"Carbamazepine","kind":"drug","role":"induces","potency":"strong","mechanismBased":false,"note":"An auto-inducer: it induces its own metabolism over the first weeks of therapy.","cites":[{"key":"fdaTable","text":"U.S. Food and Drug Administration (2023) Drug Development and Drug Interactions: Table of Substrates, Inhibitors and Inducers FDA","url":"https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-drug-interactions-table-substrates-inhibitors-and-inducers"},{"key":"flockhart","text":"Flockhart DA, Thacker D, McDonald C, Desta Z (2021) The Flockhart Cytochrome P450 Drug-Drug Interaction Table Division of Clinical Pharmacology, Indiana University School of Medicine","url":"https://drug-interactions.medicine.iu.edu"}]},{"name":"Phenytoin","kind":"drug","role":"induces","potency":"strong","mechanismBased":false,"note":"Classic CAR and PXR inducer, and itself a CYP2C9 substrate with saturable kinetics.","cites":[{"key":"fdaTable","text":"U.S. Food and Drug Administration (2023) Drug Development and Drug Interactions: Table of Substrates, Inhibitors and Inducers FDA","url":"https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-drug-interactions-table-substrates-inhibitors-and-inducers"},{"key":"flockhart","text":"Flockhart DA, Thacker D, McDonald C, Desta Z (2021) The Flockhart Cytochrome P450 Drug-Drug Interaction Table Division of Clinical Pharmacology, Indiana University School of Medicine","url":"https://drug-interactions.medicine.iu.edu"}]},{"name":"Phenobarbital","kind":"drug","role":"induces","potency":"strong","mechanismBased":false,"note":"Classic broad inducer.","cites":[{"key":"fdaTable","text":"U.S. Food and Drug Administration (2023) Drug Development and Drug Interactions: Table of Substrates, Inhibitors and Inducers FDA","url":"https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-drug-interactions-table-substrates-inhibitors-and-inducers"}]},{"name":"Primidone","kind":"drug","role":"induces","potency":"strong","mechanismBased":false,"note":"Metabolised to phenobarbital, so it inherits its induction profile.","cites":[{"key":"fdaTable","text":"U.S. Food and Drug Administration (2023) Drug Development and Drug Interactions: Table of Substrates, Inhibitors and Inducers FDA","url":"https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-drug-interactions-table-substrates-inhibitors-and-inducers"}]},{"name":"Enzalutamide","kind":"drug","role":"induces","potency":"strong","mechanismBased":false,"note":"Oncology agent with a clinically severe induction profile.","cites":[{"key":"fdaTable","text":"U.S. Food and Drug Administration (2023) Drug Development and Drug Interactions: Table of Substrates, Inhibitors and Inducers FDA","url":"https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-drug-interactions-table-substrates-inhibitors-and-inducers"}]},{"name":"Mitotane","kind":"drug","role":"induces","potency":"strong","mechanismBased":false,"note":"Profound and prolonged induction.","cites":[{"key":"fdaTable","text":"U.S. Food and Drug Administration (2023) Drug Development and Drug Interactions: Table of Substrates, Inhibitors and Inducers FDA","url":"https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-drug-interactions-table-substrates-inhibitors-and-inducers"}]},{"name":"Efavirenz","kind":"drug","role":"induces","potency":"moderate","mechanismBased":false,"note":"Complicates co-medication in HIV care.","cites":[{"key":"fdaTable","text":"U.S. Food and Drug Administration (2023) Drug Development and Drug Interactions: Table of Substrates, Inhibitors and Inducers FDA","url":"https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-drug-interactions-table-substrates-inhibitors-and-inducers"}]},{"name":"Rifabutin","kind":"drug","role":"induces","potency":"moderate","mechanismBased":false,"note":"Chosen over rifampicin specifically to reduce induction.","cites":[{"key":"fdaTable","text":"U.S. Food and Drug Administration (2023) Drug Development and Drug Interactions: Table of Substrates, Inhibitors and Inducers FDA","url":"https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-drug-interactions-table-substrates-inhibitors-and-inducers"}]},{"name":"Modafinil","kind":"drug","role":"induces","potency":"moderate","mechanismBased":false,"note":"Documented contraceptive failure signal.","cites":[{"key":"fdaTable","text":"U.S. Food and Drug Administration (2023) Drug Development and Drug Interactions: Table of Substrates, Inhibitors and Inducers FDA","url":"https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-drug-interactions-table-substrates-inhibitors-and-inducers"}]},{"name":"St John's wort (hyperforin)","kind":"botanical","role":"induces","potency":"strong","mechanismBased":false,"note":"PXR activation induces CYP3A4 and ABCB1 together. Acute heart transplant rejection from ciclosporin collapse; indinavir AUC fell by a median of about 57 percent in volunteers. Onset and offset each take one to two weeks, so stopping is also the interaction. Hyperforin content varies by product.","cites":[{"key":"moore2000","text":"Moore LB, Goodwin B, Jones SA, et al. (2000) St. John's wort induces hepatic drug metabolism through activation of the pregnane X receptor PNAS","url":"https://doi.org/10.1073/pnas.130155097"},{"key":"ruschitzka2000","text":"Ruschitzka F, Meier PJ, Turina M, Lüscher TF, Noll G (2000) Acute heart transplant rejection due to Saint John's wort The Lancet","url":"https://doi.org/10.1016/S0140-6736(99)05467-7"},{"key":"piscitelli2000","text":"Piscitelli SC, Burstein AH, Chaitt D, Alfaro RM, Falloon J (2000) Indinavir concentrations and St John's wort The Lancet","url":"https://doi.org/10.1016/S0140-6736(99)05712-8"},{"key":"henderson2002","text":"Henderson L, Yue QY, Bergquist C, Gerden B, Arlett P (2002) St John's wort (Hypericum perforatum): drug interactions and clinical outcomes British Journal of Clinical Pharmacology","url":"https://doi.org/10.1046/j.1365-2125.2002.01683.x"}]},{"name":"Schisandra","kind":"botanical","role":"induces","potency":"unclear","mechanismBased":false,"note":"PXR signal reported; direction and human magnitude inconsistent across preparations.","cites":[{"key":"moore2000","text":"Moore LB, Goodwin B, Jones SA, et al. (2000) St. John's wort induces hepatic drug metabolism through activation of the pregnane X receptor PNAS","url":"https://doi.org/10.1073/pnas.130155097"}]},{"name":"Ginkgo biloba","kind":"botanical","role":"induces","potency":"unclear","mechanismBased":false,"note":"Weak and inconsistent induction signals across studies and preparations.","cites":[{"key":"flockhart","text":"Flockhart DA, Thacker D, McDonald C, Desta Z (2021) The Flockhart Cytochrome P450 Drug-Drug Interaction Table Division of Clinical Pharmacology, Indiana University School of Medicine","url":"https://drug-interactions.medicine.iu.edu"}]}]},{"id":"cyp2c9","name":"CYP2C9","page":"/science/cyp450/cyp2c9","substrates":[{"name":"S-warfarin","nti":true,"note":"The three-to-fivefold more potent enantiomer; R-warfarin goes through CYP1A2 and CYP3A4, which is why a CYP2C9 inhibitor moves the INR far more than total warfarin concentration suggests.","cites":["holbrook2005","flockhart"]},{"name":"Phenytoin","nti":true,"note":"Saturable non-linear kinetics: a small clearance change produces a large level change near the top of the range.","cites":["flockhart","fdaTable"]},{"name":"Celecoxib","nti":false,"note":"Sensitive index substrate for this enzyme.","cites":["fdaTable","flockhart"]},{"name":"Ibuprofen","nti":false,"note":"Accumulation raises gastrointestinal bleeding and renal risk; NSAIDs also potentiate warfarin pharmacodynamically.","cites":["flockhart","holbrook2005"]},{"name":"Diclofenac","nti":false,"note":"CYP2C9 substrate NSAID.","cites":["flockhart"]},{"name":"Naproxen","nti":false,"note":"CYP2C9 substrate NSAID.","cites":["flockhart"]},{"name":"Piroxicam","nti":false,"note":"CYP2C9 substrate NSAID with a long half-life.","cites":["flockhart"]},{"name":"Meloxicam","nti":false,"note":"CYP2C9 substrate NSAID.","cites":["flockhart"]},{"name":"Flurbiprofen","nti":false,"note":"Used as an in-vitro and in-vivo CYP2C9 probe.","cites":["flockhart"]},{"name":"Glipizide","nti":false,"note":"Accumulation causes hypoglycaemia, which in an older person presents as confusion or a fall.","cites":["flockhart","fdaTable"]},{"name":"Glimepiride","nti":false,"note":"Sulfonylurea; same hypoglycaemia consequence.","cites":["flockhart"]},{"name":"Glibenclamide (glyburide)","nti":false,"note":"Sulfonylurea with a long duration of action.","cites":["flockhart"]},{"name":"Tolbutamide","nti":false,"note":"Historical CYP2C9 probe substrate.","cites":["flockhart"]},{"name":"Losartan","nti":false,"note":"A PRODRUG: CYP2C9 forms the more potent metabolite E-3174, so an inhibitor gives LESS antihypertensive effect.","cites":["flockhart","fdaTable"]},{"name":"Irbesartan","nti":false,"note":"CYP2C9 substrate with a wider margin.","cites":["flockhart"]},{"name":"Candesartan","nti":false,"note":"CYP2C9 substrate with a wider margin.","cites":["flockhart"]},{"name":"Fluvastatin","nti":false,"note":"The statin on this enzyme rather than on CYP3A4.","cites":["flockhart","fdaTable"]},{"name":"Δ9-THC","nti":false,"note":"CYP2C9 performs the 11-hydroxylation to the psychoactive 11-hydroxy-THC. Star-3 homozygotes showed roughly threefold higher oral THC exposure than star-1 homozygotes.","cites":["sachseseeboth2009","bland2005","watanabe2007"]},{"name":"Cannabidiol","nti":false,"note":"A CYP2C9 substrate as well as an inhibitor of the enzyme.","cites":["jiang2011","stout2014"]},{"name":"Sildenafil","nti":false,"note":"Multiple-pathway drug; CYP2C9 carries a minority of clearance, so the fractional contribution is low.","cites":["flockhart"]}],"inhibitors":[{"name":"Fluconazole","kind":"drug","role":"inhibits","potency":"strong","mechanismBased":false,"note":"Dose dependent; the most clinically important CYP2C9 inhibitor and a recognised cause of warfarin over-anticoagulation.","cites":[{"key":"fdaTable","text":"U.S. Food and Drug Administration (2023) Drug Development and Drug Interactions: Table of Substrates, Inhibitors and Inducers FDA","url":"https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-drug-interactions-table-substrates-inhibitors-and-inducers"},{"key":"holbrook2005","text":"Holbrook AM, Pereira JA, Labiris R, et al. (2005) Systematic Overview of Warfarin and Its Drug and Food Interactions Archives of Internal Medicine","url":"https://doi.org/10.1001/archinte.165.10.1095"},{"key":"flockhart","text":"Flockhart DA, Thacker D, McDonald C, Desta Z (2021) The Flockhart Cytochrome P450 Drug-Drug Interaction Table Division of Clinical Pharmacology, Indiana University School of Medicine","url":"https://drug-interactions.medicine.iu.edu"}]},{"name":"Miconazole (including oral gel and vaginal preparations)","kind":"drug","role":"inhibits","potency":"moderate","mechanismBased":false,"note":"Systemic absorption from topical and oral gel formulations is enough to move the INR — a documented and repeatedly missed interaction.","cites":[{"key":"holbrook2005","text":"Holbrook AM, Pereira JA, Labiris R, et al. (2005) Systematic Overview of Warfarin and Its Drug and Food Interactions Archives of Internal Medicine","url":"https://doi.org/10.1001/archinte.165.10.1095"},{"key":"flockhart","text":"Flockhart DA, Thacker D, McDonald C, Desta Z (2021) The Flockhart Cytochrome P450 Drug-Drug Interaction Table Division of Clinical Pharmacology, Indiana University School of Medicine","url":"https://drug-interactions.medicine.iu.edu"}]},{"name":"Amiodarone","kind":"drug","role":"inhibits","potency":"moderate","mechanismBased":false,"note":"Long half-life; the interaction persists for weeks after the drug is stopped.","cites":[{"key":"holbrook2005","text":"Holbrook AM, Pereira JA, Labiris R, et al. (2005) Systematic Overview of Warfarin and Its Drug and Food Interactions Archives of Internal Medicine","url":"https://doi.org/10.1001/archinte.165.10.1095"},{"key":"fdaTable","text":"U.S. Food and Drug Administration (2023) Drug Development and Drug Interactions: Table of Substrates, Inhibitors and Inducers FDA","url":"https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-drug-interactions-table-substrates-inhibitors-and-inducers"}]},{"name":"Sulfamethoxazole with trimethoprim","kind":"drug","role":"inhibits","potency":"moderate","mechanismBased":false,"note":"Classic warfarin interaction, compounded because trimethoprim also has an antifolate effect.","cites":[{"key":"holbrook2005","text":"Holbrook AM, Pereira JA, Labiris R, et al. (2005) Systematic Overview of Warfarin and Its Drug and Food Interactions Archives of Internal Medicine","url":"https://doi.org/10.1001/archinte.165.10.1095"}]},{"name":"Metronidazole","kind":"drug","role":"inhibits","potency":"moderate","mechanismBased":false,"note":"Inhibits S-warfarin metabolism specifically.","cites":[{"key":"holbrook2005","text":"Holbrook AM, Pereira JA, Labiris R, et al. (2005) Systematic Overview of Warfarin and Its Drug and Food Interactions Archives of Internal Medicine","url":"https://doi.org/10.1001/archinte.165.10.1095"},{"key":"flockhart","text":"Flockhart DA, Thacker D, McDonald C, Desta Z (2021) The Flockhart Cytochrome P450 Drug-Drug Interaction Table Division of Clinical Pharmacology, Indiana University School of Medicine","url":"https://drug-interactions.medicine.iu.edu"}]},{"name":"Valproate","kind":"drug","role":"inhibits","potency":"moderate","mechanismBased":false,"note":"Also a UGT inhibitor and a protein-binding displacer — three mechanisms in one drug.","cites":[{"key":"flockhart","text":"Flockhart DA, Thacker D, McDonald C, Desta Z (2021) The Flockhart Cytochrome P450 Drug-Drug Interaction Table Division of Clinical Pharmacology, Indiana University School of Medicine","url":"https://drug-interactions.medicine.iu.edu"},{"key":"anderson1996","text":"Anderson GD, Yau MK, Gidal BE, et al. (1996) Bidirectional interaction of valproate and lamotrigine in healthy subjects Clinical Pharmacology & Therapeutics","url":"https://doi.org/10.1016/s0009-9236(96)90130-7"}]},{"name":"Fluvoxamine","kind":"drug","role":"inhibits","potency":"moderate","mechanismBased":false,"note":"Broad inhibitor: strong at CYP1A2 and CYP2C19, moderate here.","cites":[{"key":"culmmerdek2005","text":"Culm-Merdek KE, von Moltke LL, Harmatz JS, Greenblatt DJ (2005) Fluvoxamine impairs single-dose caffeine clearance without altering caffeine pharmacodynamics British Journal of Clinical Pharmacology","url":"https://doi.org/10.1111/j.1365-2125.2005.02467.x"},{"key":"fdaTable","text":"U.S. Food and Drug Administration (2023) Drug Development and Drug Interactions: Table of Substrates, Inhibitors and Inducers FDA","url":"https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-drug-interactions-table-substrates-inhibitors-and-inducers"}]},{"name":"Fluvastatin","kind":"drug","role":"inhibits","potency":"weak","mechanismBased":false,"note":"A substrate that is also a weak inhibitor.","cites":[{"key":"flockhart","text":"Flockhart DA, Thacker D, McDonald C, Desta Z (2021) The Flockhart Cytochrome P450 Drug-Drug Interaction Table Division of Clinical Pharmacology, Indiana University School of Medicine","url":"https://drug-interactions.medicine.iu.edu"}]},{"name":"Capecitabine","kind":"drug","role":"inhibits","potency":"moderate","mechanismBased":false,"note":"A well-documented and dangerous warfarin interaction in oncology.","cites":[{"key":"holbrook2005","text":"Holbrook AM, Pereira JA, Labiris R, et al. (2005) Systematic Overview of Warfarin and Its Drug and Food Interactions Archives of Internal Medicine","url":"https://doi.org/10.1001/archinte.165.10.1095"}]},{"name":"Fluorouracil","kind":"drug","role":"inhibits","potency":"moderate","mechanismBased":false,"note":"Same warfarin interaction as capecitabine, of which it is the active moiety.","cites":[{"key":"holbrook2005","text":"Holbrook AM, Pereira JA, Labiris R, et al. (2005) Systematic Overview of Warfarin and Its Drug and Food Interactions Archives of Internal Medicine","url":"https://doi.org/10.1001/archinte.165.10.1095"}]},{"name":"Cannabidiol (CBD)","kind":"botanical","role":"inhibits","potency":"moderate","mechanismBased":false,"note":"Inhibits CYP2C9 in vitro and is a CYP2C9 substrate. Relevant at pharmaceutical doses, weakly quantified at supplement doses.","cites":[{"key":"yamaoriSeries","text":"Yamaori S, Ebisawa J, Okushima Y, Kushihara M, Okamoto Y, Yamamoto I, Watanabe K, et al. (2011) Series of in-vitro studies characterising cannabidiol, cannabinol and Δ9-THC as isoform-selective inhibitors of human CYP1, CYP2C19, CYP2D6 and CYP3A enzymes (published 2010-2012 across Life Sciences, Biochemical Pharmacology and Drug Metabolism and Disposition) Life Sciences / Biochemical Pharmacology / Drug Metabolism and Disposition [identifier unverified]","url":""},{"key":"stout2014","text":"Stout SM, Cimino NM (2014) Exogenous cannabinoids as substrates, inhibitors, and inducers of human drug metabolizing enzymes: a systematic review Drug Metabolism Reviews","url":"https://doi.org/10.3109/03602532.2013.849268"},{"key":"nasrin2021","text":"Nasrin S, Watson CJW, Perez-Paramo YX, Lazarus P (2021) Cannabinoid metabolites as inhibitors of major hepatic CYP450 enzymes, with implications for cannabis-drug interactions Drug Metabolism and Disposition","url":"https://doi.org/10.1124/dmd.121.000442"}]},{"name":"Δ9-THC","kind":"botanical","role":"inhibits","potency":"weak","mechanismBased":false,"note":"Predominantly a substrate here; weak in-vitro inhibition including from metabolites.","cites":[{"key":"nasrin2021","text":"Nasrin S, Watson CJW, Perez-Paramo YX, Lazarus P (2021) Cannabinoid metabolites as inhibitors of major hepatic CYP450 enzymes, with implications for cannabis-drug interactions Drug Metabolism and Disposition","url":"https://doi.org/10.1124/dmd.121.000442"},{"key":"stout2014","text":"Stout SM, Cimino NM (2014) Exogenous cannabinoids as substrates, inhibitors, and inducers of human drug metabolizing enzymes: a systematic review Drug Metabolism Reviews","url":"https://doi.org/10.3109/03602532.2013.849268"}]},{"name":"Curcuminoids (turmeric)","kind":"botanical","role":"inhibits","potency":"moderate","mechanismBased":false,"note":"Inhibits CYP2C9 in the same comparative study that characterises its CYP3A4, UGT and SULT effects.","cites":[{"key":"volak2008","text":"Volak LP, Ghirmai S, Cashman JR, Court MH (2008) Curcuminoids Inhibit Multiple Human Cytochromes P450, UDP-Glucuronosyltransferase, and Sulfotransferase Enzymes, whereas Piperine is a Relatively Selective CYP3A4 Inhibitor Drug Metabolism and Disposition","url":"https://doi.org/10.1124/dmd.108.020552"},{"key":"bahramsoltani2017","text":"Bahramsoltani R, Rahimi R, Farzaei MH (2017) Pharmacokinetic interactions of curcuminoids with conventional drugs: A review Journal of Ethnopharmacology","url":"https://doi.org/10.1016/j.jep.2017.07.022"}]},{"name":"Kavalactones (kava)","kind":"botanical","role":"inhibits","potency":"variable","mechanismBased":false,"note":"Potent in vitro. NOT probed in the main in-vivo human kava study, so unconfirmed rather than contradicted.","cites":[{"key":"mathews2002","text":"Mathews JM, Etheridge AS, Black SR (2002) Inhibition of human cytochrome P450 activities by kava extract and kavalactones Drug Metabolism and Disposition","url":"https://doi.org/10.1124/dmd.30.11.1153"},{"key":"zou2002","text":"Zou L, Harkey MR, Henderson GL (2002) Effects of herbal components on cDNA-expressed cytochrome P450 enzyme catalytic activity Life Sciences","url":"https://doi.org/10.1016/s0024-3205(02)01913-6"},{"key":"gurley2005","text":"Gurley BJ, Gardner SF, Hubbard MA, et al. (2005) In vivo effects of goldenseal, kava kava, black cohosh, and valerian on human cytochrome P450 1A2, 2D6, 2E1, and 3A4/5 phenotypes Clinical Pharmacology & Therapeutics","url":"https://doi.org/10.1016/j.clpt.2005.01.009"},{"key":"kavaDatasheet2026","text":"Van Kush Family Research Institute (Temple Pharmacopoeia Project) (2026) Kava Potentiators Datasheet, reconstructed from the 2020 KavaForums potentiators thread Operator corpus, MELEK knowledge base [identifier unverified]","url":""}]},{"name":"Piperine (black pepper)","kind":"botanical","role":"inhibits","potency":"weak","mechanismBased":false,"note":"Claimed as a CYP2C9 inhibitor in the operator corpus; the controlled in-vitro comparison found piperine relatively selective for CYP3A4, so low confidence.","cites":[{"key":"bhardwaj2002","text":"Bhardwaj RK, Glaeser H, Becquemont L, Klotz U, Gupta SK, Fromm MF (2002) Piperine, a Major Constituent of Black Pepper, Inhibits Human P-glycoprotein and CYP3A4 The Journal of Pharmacology and Experimental Therapeutics","url":"https://doi.org/10.1124/jpet.102.034728"},{"key":"volak2008","text":"Volak LP, Ghirmai S, Cashman JR, Court MH (2008) Curcuminoids Inhibit Multiple Human Cytochromes P450, UDP-Glucuronosyltransferase, and Sulfotransferase Enzymes, whereas Piperine is a Relatively Selective CYP3A4 Inhibitor Drug Metabolism and Disposition","url":"https://doi.org/10.1124/dmd.108.020552"},{"key":"kavaDatasheet2026","text":"Van Kush Family Research Institute (Temple Pharmacopoeia Project) (2026) Kava Potentiators Datasheet, reconstructed from the 2020 KavaForums potentiators thread Operator corpus, MELEK knowledge base [identifier unverified]","url":""}]},{"name":"Grapefruit juice","kind":"botanical","role":"inhibits","potency":"weak","mechanismBased":false,"note":"Named explicitly to be clear that the grapefruit effect is a CYP3A4 phenomenon and does not transfer meaningfully to CYP2C9.","cites":[{"key":"bailey2013","text":"Bailey DG, Dresser G, Arnold JMO (2013) Grapefruit–medication interactions: Forbidden fruit or avoidable consequences? CMAJ (published online 2012-11-26)","url":"https://doi.org/10.1503/cmaj.120951"}]},{"name":"Cranberry juice","kind":"food","role":"inhibits","potency":"unclear","mechanismBased":false,"note":"A long-running warfarin case-report literature with inconsistent controlled-study results. Listed because readers ask; marked unclear because the data are genuinely mixed.","cites":[{"key":"holbrook2005","text":"Holbrook AM, Pereira JA, Labiris R, et al. (2005) Systematic Overview of Warfarin and Its Drug and Food Interactions Archives of Internal Medicine","url":"https://doi.org/10.1001/archinte.165.10.1095"}]}],"inducers":[{"name":"Rifampicin","kind":"drug","role":"induces","potency":"strong","mechanismBased":false,"note":"Reduces warfarin effect substantially; requires re-titration in both directions.","cites":[{"key":"fdaTable","text":"U.S. Food and Drug Administration (2023) Drug Development and Drug Interactions: Table of Substrates, Inhibitors and Inducers FDA","url":"https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-drug-interactions-table-substrates-inhibitors-and-inducers"},{"key":"holbrook2005","text":"Holbrook AM, Pereira JA, Labiris R, et al. (2005) Systematic Overview of Warfarin and Its Drug and Food Interactions Archives of Internal Medicine","url":"https://doi.org/10.1001/archinte.165.10.1095"}]},{"name":"Carbamazepine","kind":"drug","role":"induces","potency":"strong","mechanismBased":false,"note":"Broad anticonvulsant induction.","cites":[{"key":"fdaTable","text":"U.S. Food and Drug Administration (2023) Drug Development and Drug Interactions: Table of Substrates, Inhibitors and Inducers FDA","url":"https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-drug-interactions-table-substrates-inhibitors-and-inducers"},{"key":"flockhart","text":"Flockhart DA, Thacker D, McDonald C, Desta Z (2021) The Flockhart Cytochrome P450 Drug-Drug Interaction Table Division of Clinical Pharmacology, Indiana University School of Medicine","url":"https://drug-interactions.medicine.iu.edu"}]},{"name":"Phenytoin","kind":"drug","role":"induces","potency":"moderate","mechanismBased":false,"note":"Both induces CYP2C9 and is a substrate of it, which makes its own kinetics messy.","cites":[{"key":"flockhart","text":"Flockhart DA, Thacker D, McDonald C, Desta Z (2021) The Flockhart Cytochrome P450 Drug-Drug Interaction Table Division of Clinical Pharmacology, Indiana University School of Medicine","url":"https://drug-interactions.medicine.iu.edu"},{"key":"fdaTable","text":"U.S. Food and Drug Administration (2023) Drug Development and Drug Interactions: Table of Substrates, Inhibitors and Inducers FDA","url":"https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-drug-interactions-table-substrates-inhibitors-and-inducers"}]},{"name":"Phenobarbital","kind":"drug","role":"induces","potency":"moderate","mechanismBased":false,"note":"Classic CAR-mediated induction.","cites":[{"key":"fdaTable","text":"U.S. Food and Drug Administration (2023) Drug Development and Drug Interactions: Table of Substrates, Inhibitors and Inducers FDA","url":"https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-drug-interactions-table-substrates-inhibitors-and-inducers"}]},{"name":"Enzalutamide","kind":"drug","role":"induces","potency":"moderate","mechanismBased":false,"note":"Broad induction reaching this isoform.","cites":[{"key":"fdaTable","text":"U.S. Food and Drug Administration (2023) Drug Development and Drug Interactions: Table of Substrates, Inhibitors and Inducers FDA","url":"https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-drug-interactions-table-substrates-inhibitors-and-inducers"}]},{"name":"Ritonavir","kind":"drug","role":"induces","potency":"moderate","mechanismBased":false,"note":"Inhibits CYP3A4 and induces CYP2C9 — opposite directions on different enzymes in one drug.","cites":[{"key":"fdaTable","text":"U.S. Food and Drug Administration (2023) Drug Development and Drug Interactions: Table of Substrates, Inhibitors and Inducers FDA","url":"https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-drug-interactions-table-substrates-inhibitors-and-inducers"}]},{"name":"St John's wort (hyperforin)","kind":"botanical","role":"induces","potency":"moderate","mechanismBased":false,"note":"Part of the same PXR programme as its CYP3A4 and P-glycoprotein induction; associated with loss of warfarin control.","cites":[{"key":"moore2000","text":"Moore LB, Goodwin B, Jones SA, et al. (2000) St. John's wort induces hepatic drug metabolism through activation of the pregnane X receptor PNAS","url":"https://doi.org/10.1073/pnas.130155097"},{"key":"henderson2002","text":"Henderson L, Yue QY, Bergquist C, Gerden B, Arlett P (2002) St John's wort (Hypericum perforatum): drug interactions and clinical outcomes British Journal of Clinical Pharmacology","url":"https://doi.org/10.1046/j.1365-2125.2002.01683.x"},{"key":"holbrook2005","text":"Holbrook AM, Pereira JA, Labiris R, et al. (2005) Systematic Overview of Warfarin and Its Drug and Food Interactions Archives of Internal Medicine","url":"https://doi.org/10.1001/archinte.165.10.1095"}]}]},{"id":"cyp2c19","name":"CYP2C19","page":"/science/cyp450/cyp2c19","substrates":[{"name":"Clopidogrel","nti":false,"note":"A PRODRUG requiring CYP2C19 for bioactivation. Inhibition or poor-metaboliser genotype means less platelet inhibition and more stent thrombosis — an FDA boxed warning.","cites":["mega2009","fdaTable"]},{"name":"Omeprazole","nti":false,"note":"Substrate AND inhibitor of the enzyme that clears it; the basis of the clopidogrel and PPI controversy.","cites":["desta2002","fdaTable"]},{"name":"Esomeprazole","nti":false,"note":"The S-enantiomer of omeprazole; same relationship.","cites":["fdaTable"]},{"name":"Lansoprazole","nti":false,"note":"CYP2C19 substrate PPI.","cites":["flockhart"]},{"name":"Clobazam","nti":false,"note":"Parent via CYP3A4; the active N-desmethylclobazam metabolite is cleared by CYP2C19 and accumulates when it is inhibited. The cannabidiol interaction runs here.","cites":["geffrey2015","morrison2019"]},{"name":"Diazepam","nti":false,"note":"N-demethylation to the long-lived nordiazepam; poor metabolisers are markedly more sedated.","cites":["desta2002","flockhart"]},{"name":"Voriconazole","nti":true,"note":"Highly variable exposure driven by genotype; both subtherapeutic failure and neurotoxic accumulation occur, which is why plasma concentrations are measured.","cites":["desta2002","fdaTable"]},{"name":"Citalopram and escitalopram","nti":false,"note":"Poor metabolisers reach higher exposure, and the dose-dependent QT prolongation that caps citalopram dosing makes that matter.","cites":["desta2002","crediblemeds","roden2004"]},{"name":"Sertraline","nti":false,"note":"Partial CYP2C19 clearance.","cites":["flockhart"]},{"name":"Amitriptyline","nti":true,"note":"Demethylation to nortriptyline runs through CYP2C19; the tricyclics have a narrow margin.","cites":["flockhart"]},{"name":"Phenytoin","nti":true,"note":"A minor route compared with CYP2C9, but it becomes more important when CYP2C9 is saturated or inhibited.","cites":["flockhart"]},{"name":"Proguanil","nti":false,"note":"A PRODRUG activated by CYP2C19 to cycloguanil — another prodrug inversion.","cites":["flockhart"]},{"name":"Cannabidiol","nti":false,"note":"CYP2C19 is a principal oxidative route for CBD, and CBD inhibits the same enzyme.","cites":["jiang2011","yamaoriSeries","stout2014"]},{"name":"Carisoprodol","nti":false,"note":"CYP2C19 substrate.","cites":["flockhart"]},{"name":"Cyclophosphamide","nti":false,"note":"Partial CYP2C19 contribution to its bioactivation.","cites":["flockhart"]}],"inhibitors":[{"name":"Fluvoxamine","kind":"drug","role":"inhibits","potency":"strong","mechanismBased":false,"note":"Strong at CYP2C19 and strong at CYP1A2 simultaneously; the broadest-spectrum SSRI inhibitor.","cites":[{"key":"fdaTable","text":"U.S. Food and Drug Administration (2023) Drug Development and Drug Interactions: Table of Substrates, Inhibitors and Inducers FDA","url":"https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-drug-interactions-table-substrates-inhibitors-and-inducers"},{"key":"culmmerdek2005","text":"Culm-Merdek KE, von Moltke LL, Harmatz JS, Greenblatt DJ (2005) Fluvoxamine impairs single-dose caffeine clearance without altering caffeine pharmacodynamics British Journal of Clinical Pharmacology","url":"https://doi.org/10.1111/j.1365-2125.2005.02467.x"},{"key":"flockhart","text":"Flockhart DA, Thacker D, McDonald C, Desta Z (2021) The Flockhart Cytochrome P450 Drug-Drug Interaction Table Division of Clinical Pharmacology, Indiana University School of Medicine","url":"https://drug-interactions.medicine.iu.edu"}]},{"name":"Ticlopidine","kind":"drug","role":"inhibits","potency":"strong","mechanismBased":false,"note":"Reference strong CYP2C19 inhibitor; largely superseded clinically but retained as the index inhibitor.","cites":[{"key":"fdaTable","text":"U.S. Food and Drug Administration (2023) Drug Development and Drug Interactions: Table of Substrates, Inhibitors and Inducers FDA","url":"https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-drug-interactions-table-substrates-inhibitors-and-inducers"},{"key":"flockhart","text":"Flockhart DA, Thacker D, McDonald C, Desta Z (2021) The Flockhart Cytochrome P450 Drug-Drug Interaction Table Division of Clinical Pharmacology, Indiana University School of Medicine","url":"https://drug-interactions.medicine.iu.edu"}]},{"name":"Fluconazole","kind":"drug","role":"inhibits","potency":"strong","mechanismBased":false,"note":"Strong here and moderate to strong at CYP2C9 — two narrow-index axes from one antifungal.","cites":[{"key":"fdaTable","text":"U.S. Food and Drug Administration (2023) Drug Development and Drug Interactions: Table of Substrates, Inhibitors and Inducers FDA","url":"https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-drug-interactions-table-substrates-inhibitors-and-inducers"},{"key":"flockhart","text":"Flockhart DA, Thacker D, McDonald C, Desta Z (2021) The Flockhart Cytochrome P450 Drug-Drug Interaction Table Division of Clinical Pharmacology, Indiana University School of Medicine","url":"https://drug-interactions.medicine.iu.edu"}]},{"name":"Omeprazole","kind":"drug","role":"inhibits","potency":"moderate","mechanismBased":false,"note":"Substrate and inhibitor; the basis of the historical clopidogrel and PPI controversy.","cites":[{"key":"fdaTable","text":"U.S. Food and Drug Administration (2023) Drug Development and Drug Interactions: Table of Substrates, Inhibitors and Inducers FDA","url":"https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-drug-interactions-table-substrates-inhibitors-and-inducers"},{"key":"mega2009","text":"Mega JL, Close SL, Wiviott SD, et al. (2009) Cytochrome P-450 polymorphisms and response to clopidogrel New England Journal of Medicine","url":"https://doi.org/10.1016/j.jvs.2009.02.023"}]},{"name":"Esomeprazole","kind":"drug","role":"inhibits","potency":"moderate","mechanismBased":false,"note":"Same relationship as omeprazole.","cites":[{"key":"fdaTable","text":"U.S. Food and Drug Administration (2023) Drug Development and Drug Interactions: Table of Substrates, Inhibitors and Inducers FDA","url":"https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-drug-interactions-table-substrates-inhibitors-and-inducers"}]},{"name":"Fluoxetine","kind":"drug","role":"inhibits","potency":"moderate","mechanismBased":false,"note":"Plus strong CYP2D6 inhibition, and a metabolite with a one to two week half-life, so the effect long outlasts the last dose.","cites":[{"key":"fdaTable","text":"U.S. Food and Drug Administration (2023) Drug Development and Drug Interactions: Table of Substrates, Inhibitors and Inducers FDA","url":"https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-drug-interactions-table-substrates-inhibitors-and-inducers"},{"key":"flockhart","text":"Flockhart DA, Thacker D, McDonald C, Desta Z (2021) The Flockhart Cytochrome P450 Drug-Drug Interaction Table Division of Clinical Pharmacology, Indiana University School of Medicine","url":"https://drug-interactions.medicine.iu.edu"}]},{"name":"Voriconazole","kind":"drug","role":"inhibits","potency":"moderate","mechanismBased":false,"note":"Substrate and inhibitor.","cites":[{"key":"fdaTable","text":"U.S. Food and Drug Administration (2023) Drug Development and Drug Interactions: Table of Substrates, Inhibitors and Inducers FDA","url":"https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-drug-interactions-table-substrates-inhibitors-and-inducers"}]},{"name":"Cimetidine","kind":"drug","role":"inhibits","potency":"weak","mechanismBased":false,"note":"Broad weak inhibition; the other H2 blockers do not share it.","cites":[{"key":"flockhart","text":"Flockhart DA, Thacker D, McDonald C, Desta Z (2021) The Flockhart Cytochrome P450 Drug-Drug Interaction Table Division of Clinical Pharmacology, Indiana University School of Medicine","url":"https://drug-interactions.medicine.iu.edu"}]},{"name":"Moclobemide","kind":"drug","role":"inhibits","potency":"moderate","mechanismBased":false,"note":"Documented moderate CYP2C19 inhibitor as well as a reversible MAO-A inhibitor.","cites":[{"key":"flockhart","text":"Flockhart DA, Thacker D, McDonald C, Desta Z (2021) The Flockhart Cytochrome P450 Drug-Drug Interaction Table Division of Clinical Pharmacology, Indiana University School of Medicine","url":"https://drug-interactions.medicine.iu.edu"}]},{"name":"Felbamate","kind":"drug","role":"inhibits","potency":"moderate","mechanismBased":false,"note":"Documented moderate inhibitor.","cites":[{"key":"flockhart","text":"Flockhart DA, Thacker D, McDonald C, Desta Z (2021) The Flockhart Cytochrome P450 Drug-Drug Interaction Table Division of Clinical Pharmacology, Indiana University School of Medicine","url":"https://drug-interactions.medicine.iu.edu"}]},{"name":"Ketoconazole","kind":"drug","role":"inhibits","potency":"moderate","mechanismBased":false,"note":"Moderate at CYP2C19, strong at CYP3A4.","cites":[{"key":"fdaTable","text":"U.S. Food and Drug Administration (2023) Drug Development and Drug Interactions: Table of Substrates, Inhibitors and Inducers FDA","url":"https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-drug-interactions-table-substrates-inhibitors-and-inducers"}]},{"name":"Cannabidiol (CBD)","kind":"botanical","role":"inhibits","potency":"moderate","mechanismBased":false,"note":"Documented in humans at pharmaceutical doses: raises N-desmethylclobazam several-fold, with sedation requiring clobazam dose reduction. Also a CYP2C19 substrate. Should NOT be extrapolated unchanged to low-dose consumer CBD.","cites":[{"key":"geffrey2015","text":"Geffrey AL, Pollack SF, Bruno PL, Thiele EA (2015) Drug-drug interaction between clobazam and cannabidiol in children with refractory epilepsy Epilepsia","url":"https://doi.org/10.1111/epi.13060"},{"key":"morrison2019","text":"Morrison G, Crockett J, Blakey G, Sommerville K (2019) A phase 1, open-label, pharmacokinetic trial to investigate possible drug-drug interactions between clobazam, stiripentol, or valproate and cannabidiol in healthy subjects Clinical Pharmacology in Drug Development","url":"https://doi.org/10.1002/cpdd.665"},{"key":"yamaoriSeries","text":"Yamaori S, Ebisawa J, Okushima Y, Kushihara M, Okamoto Y, Yamamoto I, Watanabe K, et al. (2011) Series of in-vitro studies characterising cannabidiol, cannabinol and Δ9-THC as isoform-selective inhibitors of human CYP1, CYP2C19, CYP2D6 and CYP3A enzymes (published 2010-2012 across Life Sciences, Biochemical Pharmacology and Drug Metabolism and Disposition) Life Sciences / Biochemical Pharmacology / Drug Metabolism and Disposition [identifier unverified]","url":""},{"key":"stout2014","text":"Stout SM, Cimino NM (2014) Exogenous cannabinoids as substrates, inhibitors, and inducers of human drug metabolizing enzymes: a systematic review Drug Metabolism Reviews","url":"https://doi.org/10.3109/03602532.2013.849268"}]},{"name":"Δ9-THC","kind":"botanical","role":"inhibits","potency":"weak","mechanismBased":false,"note":"In-vitro inhibition reported; not established as clinically meaningful at this isoform.","cites":[{"key":"yamaoriSeries","text":"Yamaori S, Ebisawa J, Okushima Y, Kushihara M, Okamoto Y, Yamamoto I, Watanabe K, et al. (2011) Series of in-vitro studies characterising cannabidiol, cannabinol and Δ9-THC as isoform-selective inhibitors of human CYP1, CYP2C19, CYP2D6 and CYP3A enzymes (published 2010-2012 across Life Sciences, Biochemical Pharmacology and Drug Metabolism and Disposition) Life Sciences / Biochemical Pharmacology / Drug Metabolism and Disposition [identifier unverified]","url":""},{"key":"nasrin2021","text":"Nasrin S, Watson CJW, Perez-Paramo YX, Lazarus P (2021) Cannabinoid metabolites as inhibitors of major hepatic CYP450 enzymes, with implications for cannabis-drug interactions Drug Metabolism and Disposition","url":"https://doi.org/10.1124/dmd.121.000442"}]},{"name":"Kavalactones (kava)","kind":"botanical","role":"inhibits","potency":"variable","mechanismBased":false,"note":"Reported potent in vitro and named in the operator corpus; NOT probed in the main in-vivo human kava study, so unconfirmed in vivo.","cites":[{"key":"mathews2002","text":"Mathews JM, Etheridge AS, Black SR (2002) Inhibition of human cytochrome P450 activities by kava extract and kavalactones Drug Metabolism and Disposition","url":"https://doi.org/10.1124/dmd.30.11.1153"},{"key":"zou2002","text":"Zou L, Harkey MR, Henderson GL (2002) Effects of herbal components on cDNA-expressed cytochrome P450 enzyme catalytic activity Life Sciences","url":"https://doi.org/10.1016/s0024-3205(02)01913-6"},{"key":"gurley2005","text":"Gurley BJ, Gardner SF, Hubbard MA, et al. (2005) In vivo effects of goldenseal, kava kava, black cohosh, and valerian on human cytochrome P450 1A2, 2D6, 2E1, and 3A4/5 phenotypes Clinical Pharmacology & Therapeutics","url":"https://doi.org/10.1016/j.clpt.2005.01.009"},{"key":"kavaDatasheet2026","text":"Van Kush Family Research Institute (Temple Pharmacopoeia Project) (2026) Kava Potentiators Datasheet, reconstructed from the 2020 KavaForums potentiators thread Operator corpus, MELEK knowledge base [identifier unverified]","url":""}]},{"name":"Curcuminoids (turmeric)","kind":"botanical","role":"inhibits","potency":"weak","mechanismBased":false,"note":"Part of the broad curcuminoid CYP inhibition profile; human relevance limited by bioavailability.","cites":[{"key":"volak2008","text":"Volak LP, Ghirmai S, Cashman JR, Court MH (2008) Curcuminoids Inhibit Multiple Human Cytochromes P450, UDP-Glucuronosyltransferase, and Sulfotransferase Enzymes, whereas Piperine is a Relatively Selective CYP3A4 Inhibitor Drug Metabolism and Disposition","url":"https://doi.org/10.1124/dmd.108.020552"},{"key":"bahramsoltani2017","text":"Bahramsoltani R, Rahimi R, Farzaei MH (2017) Pharmacokinetic interactions of curcuminoids with conventional drugs: A review Journal of Ethnopharmacology","url":"https://doi.org/10.1016/j.jep.2017.07.022"}]},{"name":"Grapefruit juice","kind":"botanical","role":"inhibits","potency":"weak","mechanismBased":false,"note":"Named explicitly: the grapefruit effect does not transfer meaningfully to CYP2C19.","cites":[{"key":"bailey2013","text":"Bailey DG, Dresser G, Arnold JMO (2013) Grapefruit–medication interactions: Forbidden fruit or avoidable consequences? CMAJ (published online 2012-11-26)","url":"https://doi.org/10.1503/cmaj.120951"}]},{"name":"Goldenseal (berberine, hydrastine)","kind":"botanical","role":"inhibits","potency":"unclear","mechanismBased":false,"note":"The in-vivo human probe study tested CYP1A2, CYP2D6, CYP2E1 and CYP3A4/5, not CYP2C19, so this isoform is simply untested for goldenseal.","cites":[{"key":"gurley2005","text":"Gurley BJ, Gardner SF, Hubbard MA, et al. (2005) In vivo effects of goldenseal, kava kava, black cohosh, and valerian on human cytochrome P450 1A2, 2D6, 2E1, and 3A4/5 phenotypes Clinical Pharmacology & Therapeutics","url":"https://doi.org/10.1016/j.clpt.2005.01.009"}]}],"inducers":[{"name":"Rifampicin","kind":"drug","role":"induces","potency":"strong","mechanismBased":false,"note":"Reduces exposure of CYP2C19 substrates substantially.","cites":[{"key":"fdaTable","text":"U.S. Food and Drug Administration (2023) Drug Development and Drug Interactions: Table of Substrates, Inhibitors and Inducers FDA","url":"https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-drug-interactions-table-substrates-inhibitors-and-inducers"}]},{"name":"Carbamazepine","kind":"drug","role":"induces","potency":"moderate","mechanismBased":false,"note":"Classic broad anticonvulsant induction.","cites":[{"key":"fdaTable","text":"U.S. Food and Drug Administration (2023) Drug Development and Drug Interactions: Table of Substrates, Inhibitors and Inducers FDA","url":"https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-drug-interactions-table-substrates-inhibitors-and-inducers"},{"key":"flockhart","text":"Flockhart DA, Thacker D, McDonald C, Desta Z (2021) The Flockhart Cytochrome P450 Drug-Drug Interaction Table Division of Clinical Pharmacology, Indiana University School of Medicine","url":"https://drug-interactions.medicine.iu.edu"}]},{"name":"Phenytoin","kind":"drug","role":"induces","potency":"moderate","mechanismBased":false,"note":"Broad induction; also a partial substrate of this isoform.","cites":[{"key":"flockhart","text":"Flockhart DA, Thacker D, McDonald C, Desta Z (2021) The Flockhart Cytochrome P450 Drug-Drug Interaction Table Division of Clinical Pharmacology, Indiana University School of Medicine","url":"https://drug-interactions.medicine.iu.edu"}]},{"name":"Phenobarbital","kind":"drug","role":"induces","potency":"moderate","mechanismBased":false,"note":"Classic CAR-mediated induction.","cites":[{"key":"fdaTable","text":"U.S. Food and Drug Administration (2023) Drug Development and Drug Interactions: Table of Substrates, Inhibitors and Inducers FDA","url":"https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-drug-interactions-table-substrates-inhibitors-and-inducers"}]},{"name":"Ritonavir","kind":"drug","role":"induces","potency":"moderate","mechanismBased":false,"note":"Induction here alongside inhibition elsewhere in the same molecule.","cites":[{"key":"fdaTable","text":"U.S. Food and Drug Administration (2023) Drug Development and Drug Interactions: Table of Substrates, Inhibitors and Inducers FDA","url":"https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-drug-interactions-table-substrates-inhibitors-and-inducers"}]},{"name":"Efavirenz","kind":"drug","role":"induces","potency":"moderate","mechanismBased":false,"note":"Broad antiretroviral induction.","cites":[{"key":"fdaTable","text":"U.S. Food and Drug Administration (2023) Drug Development and Drug Interactions: Table of Substrates, Inhibitors and Inducers FDA","url":"https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-drug-interactions-table-substrates-inhibitors-and-inducers"}]},{"name":"St John's wort (hyperforin)","kind":"botanical","role":"induces","potency":"weak","mechanismBased":false,"note":"Modest CYP2C19 induction alongside its much stronger CYP3A4 and P-glycoprotein effect.","cites":[{"key":"moore2000","text":"Moore LB, Goodwin B, Jones SA, et al. (2000) St. John's wort induces hepatic drug metabolism through activation of the pregnane X receptor PNAS","url":"https://doi.org/10.1073/pnas.130155097"},{"key":"henderson2002","text":"Henderson L, Yue QY, Bergquist C, Gerden B, Arlett P (2002) St John's wort (Hypericum perforatum): drug interactions and clinical outcomes British Journal of Clinical Pharmacology","url":"https://doi.org/10.1046/j.1365-2125.2002.01683.x"}]}]},{"id":"cyp2d6","name":"CYP2D6","page":"/science/cyp450/cyp2d6","substrates":[{"name":"Codeine","nti":true,"note":"A PRODRUG converted to morphine. Poor metaboliser equals no analgesia; ultra-rapid metaboliser equals morphine toxicity, including a reported fatal poisoning in a breastfed neonate.","cites":["gasche2004","koren2006","crews2021codeine"]},{"name":"Tramadol","nti":false,"note":"A PRODRUG converted to the far more potent O-desmethyltramadol. An inhibitor removes analgesia while leaving the serotonergic and seizure-threshold effects of the parent intact.","cites":["crews2021codeine","flockhart"]},{"name":"Tamoxifen","nti":false,"note":"A PRODRUG converted to endoxifen. The metabolic pathway is not in doubt; the outcome association with genotype is genuinely contested.","cites":["jin2005","regan2012"]},{"name":"Flecainide","nti":true,"note":"Accumulation is proarrhythmic; among the highest-consequence CYP2D6 substrates.","cites":["flockhart","fdaTable"]},{"name":"Propafenone","nti":true,"note":"Antiarrhythmic with the same proarrhythmic accumulation risk.","cites":["flockhart"]},{"name":"Metoprolol","nti":false,"note":"Accumulation gives bradycardia, fatigue and loss of beta-1 selectivity. Bisoprolol and atenolol do not depend on CYP2D6.","cites":["flockhart","fdaTable"]},{"name":"Nortriptyline","nti":true,"note":"Narrow margin with cardiac and anticholinergic toxicity.","cites":["flockhart"]},{"name":"Amitriptyline","nti":true,"note":"Tricyclic with a narrow margin; also demethylated via CYP2C19.","cites":["flockhart"]},{"name":"Imipramine","nti":true,"note":"Tricyclic; CYP2D6 hydroxylation of it and of its metabolite desipramine.","cites":["flockhart"]},{"name":"Desipramine","nti":true,"note":"The classical CYP2D6 tricyclic substrate.","cites":["flockhart"]},{"name":"Risperidone","nti":false,"note":"Accumulation gives extrapyramidal effects.","cites":["flockhart"]},{"name":"Aripiprazole","nti":false,"note":"Label carries CYP2D6 dose guidance.","cites":["fdaTable"]},{"name":"Haloperidol","nti":false,"note":"Partial CYP2D6 clearance; extrapyramidal and QT consequences.","cites":["flockhart","crediblemeds"]},{"name":"Thioridazine","nti":true,"note":"QT prolongation plus CYP2D6 dependence was part of why it was withdrawn in many markets.","cites":["crediblemeds","flockhart"]},{"name":"Atomoxetine","nti":false,"note":"Exposure differs roughly ten-fold between poor and normal metabolisers; the label carries genotype guidance.","cites":["fdaTable","flockhart"]},{"name":"Venlafaxine","nti":false,"note":"Substrate and weak inhibitor.","cites":["flockhart"]},{"name":"Paroxetine","nti":false,"note":"A substrate that inhibits the enzyme clearing it, mechanism-based, so its own kinetics are non-linear.","cites":["fdaTable","flockhart"]},{"name":"Fluoxetine","nti":false,"note":"Substrate and strong inhibitor.","cites":["fdaTable"]},{"name":"Duloxetine","nti":false,"note":"CYP1A2 and CYP2D6 substrate, so two axes at once.","cites":["flockhart"]},{"name":"Dextromethorphan","nti":false,"note":"The archetypal CYP2D6 probe substrate, and an over-the-counter product that therefore never appears on a medication list.","cites":["flockhart","fdaTable"]},{"name":"Ondansetron","nti":false,"note":"Ultra-rapid metabolisers get less antiemetic effect.","cites":["flockhart"]},{"name":"Tropisetron","nti":false,"note":"Same antiemetic genotype relationship as ondansetron.","cites":["flockhart"]},{"name":"Tamsulosin","nti":false,"note":"CYP2D6 and CYP3A4 substrate.","cites":["flockhart"]},{"name":"Mexiletine","nti":false,"note":"Substrate and a moderate CYP1A2 inhibitor.","cites":["flockhart"]},{"name":"Perhexiline","nti":true,"note":"Toxicity in poor metabolisers is one of the oldest documented pharmacogenetic catastrophes.","cites":["zanger2013"]},{"name":"Psilocin","nti":false,"note":"A CYP2D6 substrate alongside glucuronidation — the pharmacological basis of the potentiation claims in the plant-medicine corpus, and it cuts both ways.","cites":["flockhart"]}],"inhibitors":[{"name":"Quinidine","kind":"drug","role":"inhibits","potency":"strong","mechanismBased":false,"note":"The reference strong inhibitor; used experimentally to phenoconvert volunteers into poor metabolisers.","cites":[{"key":"fdaTable","text":"U.S. Food and Drug Administration (2023) Drug Development and Drug Interactions: Table of Substrates, Inhibitors and Inducers FDA","url":"https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-drug-interactions-table-substrates-inhibitors-and-inducers"},{"key":"flockhart","text":"Flockhart DA, Thacker D, McDonald C, Desta Z (2021) The Flockhart Cytochrome P450 Drug-Drug Interaction Table Division of Clinical Pharmacology, Indiana University School of Medicine","url":"https://drug-interactions.medicine.iu.edu"}]},{"name":"Paroxetine","kind":"drug","role":"inhibits","potency":"strong","mechanismBased":true,"note":"Mechanism-based: inhibition deepens with repeated dosing and outlasts the drug.","cites":[{"key":"fdaTable","text":"U.S. Food and Drug Administration (2023) Drug Development and Drug Interactions: Table of Substrates, Inhibitors and Inducers FDA","url":"https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-drug-interactions-table-substrates-inhibitors-and-inducers"},{"key":"orr2012","text":"Orr STM, Ripp SL, Ballard TE, et al. (2012) Mechanism-based inactivation (MBI) of cytochrome P450 enzymes: structure-activity relationships and discovery strategies to mitigate drug-drug interaction risks Journal of Medicinal Chemistry","url":"https://doi.org/10.1021/jm300065h"}]},{"name":"Fluoxetine","kind":"drug","role":"inhibits","potency":"strong","mechanismBased":false,"note":"Norfluoxetine has a one to two week half-life, so the inhibition persists for weeks after stopping.","cites":[{"key":"fdaTable","text":"U.S. Food and Drug Administration (2023) Drug Development and Drug Interactions: Table of Substrates, Inhibitors and Inducers FDA","url":"https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-drug-interactions-table-substrates-inhibitors-and-inducers"},{"key":"flockhart","text":"Flockhart DA, Thacker D, McDonald C, Desta Z (2021) The Flockhart Cytochrome P450 Drug-Drug Interaction Table Division of Clinical Pharmacology, Indiana University School of Medicine","url":"https://drug-interactions.medicine.iu.edu"}]},{"name":"Bupropion","kind":"drug","role":"inhibits","potency":"strong","mechanismBased":false,"note":"Frequently overlooked because it is not serotonergic and is often thought of as a clean drug.","cites":[{"key":"fdaTable","text":"U.S. Food and Drug Administration (2023) Drug Development and Drug Interactions: Table of Substrates, Inhibitors and Inducers FDA","url":"https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-drug-interactions-table-substrates-inhibitors-and-inducers"},{"key":"flockhart","text":"Flockhart DA, Thacker D, McDonald C, Desta Z (2021) The Flockhart Cytochrome P450 Drug-Drug Interaction Table Division of Clinical Pharmacology, Indiana University School of Medicine","url":"https://drug-interactions.medicine.iu.edu"}]},{"name":"Terbinafine","kind":"drug","role":"inhibits","potency":"strong","mechanismBased":false,"note":"An oral antifungal taken for months for nail infection, that nobody counts as a psychotropic interaction.","cites":[{"key":"fdaTable","text":"U.S. Food and Drug Administration (2023) Drug Development and Drug Interactions: Table of Substrates, Inhibitors and Inducers FDA","url":"https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-drug-interactions-table-substrates-inhibitors-and-inducers"},{"key":"flockhart","text":"Flockhart DA, Thacker D, McDonald C, Desta Z (2021) The Flockhart Cytochrome P450 Drug-Drug Interaction Table Division of Clinical Pharmacology, Indiana University School of Medicine","url":"https://drug-interactions.medicine.iu.edu"}]},{"name":"Duloxetine","kind":"drug","role":"inhibits","potency":"moderate","mechanismBased":false,"note":"Moderate inhibitor stated on the label.","cites":[{"key":"fdaTable","text":"U.S. Food and Drug Administration (2023) Drug Development and Drug Interactions: Table of Substrates, Inhibitors and Inducers FDA","url":"https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-drug-interactions-table-substrates-inhibitors-and-inducers"}]},{"name":"Cinacalcet","kind":"drug","role":"inhibits","potency":"moderate","mechanismBased":false,"note":"Moderate inhibitor stated on the label.","cites":[{"key":"fdaTable","text":"U.S. Food and Drug Administration (2023) Drug Development and Drug Interactions: Table of Substrates, Inhibitors and Inducers FDA","url":"https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-drug-interactions-table-substrates-inhibitors-and-inducers"}]},{"name":"Mirabegron","kind":"drug","role":"inhibits","potency":"moderate","mechanismBased":false,"note":"Moderate inhibitor stated on the label.","cites":[{"key":"fdaTable","text":"U.S. Food and Drug Administration (2023) Drug Development and Drug Interactions: Table of Substrates, Inhibitors and Inducers FDA","url":"https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-drug-interactions-table-substrates-inhibitors-and-inducers"}]},{"name":"Sertraline","kind":"drug","role":"inhibits","potency":"weak","mechanismBased":false,"note":"Listed to be explicit: one of the SSRIs that largely avoids the CYP2D6 problem.","cites":[{"key":"fdaTable","text":"U.S. Food and Drug Administration (2023) Drug Development and Drug Interactions: Table of Substrates, Inhibitors and Inducers FDA","url":"https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-drug-interactions-table-substrates-inhibitors-and-inducers"},{"key":"flockhart","text":"Flockhart DA, Thacker D, McDonald C, Desta Z (2021) The Flockhart Cytochrome P450 Drug-Drug Interaction Table Division of Clinical Pharmacology, Indiana University School of Medicine","url":"https://drug-interactions.medicine.iu.edu"}]},{"name":"Citalopram and escitalopram","kind":"drug","role":"inhibits","potency":"weak","mechanismBased":false,"note":"Listed to be explicit: weak CYP2D6 inhibitors.","cites":[{"key":"fdaTable","text":"U.S. Food and Drug Administration (2023) Drug Development and Drug Interactions: Table of Substrates, Inhibitors and Inducers FDA","url":"https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-drug-interactions-table-substrates-inhibitors-and-inducers"}]},{"name":"Amiodarone","kind":"drug","role":"inhibits","potency":"weak","mechanismBased":false,"note":"Weak but very long-lasting.","cites":[{"key":"flockhart","text":"Flockhart DA, Thacker D, McDonald C, Desta Z (2021) The Flockhart Cytochrome P450 Drug-Drug Interaction Table Division of Clinical Pharmacology, Indiana University School of Medicine","url":"https://drug-interactions.medicine.iu.edu"}]},{"name":"Celecoxib","kind":"drug","role":"inhibits","potency":"weak","mechanismBased":false,"note":"Weak inhibitor that can still matter for a narrow-index substrate.","cites":[{"key":"flockhart","text":"Flockhart DA, Thacker D, McDonald C, Desta Z (2021) The Flockhart Cytochrome P450 Drug-Drug Interaction Table Division of Clinical Pharmacology, Indiana University School of Medicine","url":"https://drug-interactions.medicine.iu.edu"}]},{"name":"Cimetidine","kind":"drug","role":"inhibits","potency":"weak","mechanismBased":false,"note":"Broad weak inhibition.","cites":[{"key":"flockhart","text":"Flockhart DA, Thacker D, McDonald C, Desta Z (2021) The Flockhart Cytochrome P450 Drug-Drug Interaction Table Division of Clinical Pharmacology, Indiana University School of Medicine","url":"https://drug-interactions.medicine.iu.edu"}]},{"name":"Ranitidine","kind":"drug","role":"inhibits","potency":"weak","mechanismBased":false,"note":"Weak inhibition reported.","cites":[{"key":"flockhart","text":"Flockhart DA, Thacker D, McDonald C, Desta Z (2021) The Flockhart Cytochrome P450 Drug-Drug Interaction Table Division of Clinical Pharmacology, Indiana University School of Medicine","url":"https://drug-interactions.medicine.iu.edu"}]},{"name":"Hydroxychloroquine","kind":"drug","role":"inhibits","potency":"weak","mechanismBased":false,"note":"Weak inhibitor.","cites":[{"key":"flockhart","text":"Flockhart DA, Thacker D, McDonald C, Desta Z (2021) The Flockhart Cytochrome P450 Drug-Drug Interaction Table Division of Clinical Pharmacology, Indiana University School of Medicine","url":"https://drug-interactions.medicine.iu.edu"}]},{"name":"Goldenseal (berberine, hydrastine)","kind":"botanical","role":"inhibits","potency":"moderate","mechanismBased":false,"note":"Significant CYP2D6 inhibition in a 28-day in-vivo human probe study — the best-evidenced botanical entry on this isoform.","cites":[{"key":"gurley2005","text":"Gurley BJ, Gardner SF, Hubbard MA, et al. (2005) In vivo effects of goldenseal, kava kava, black cohosh, and valerian on human cytochrome P450 1A2, 2D6, 2E1, and 3A4/5 phenotypes Clinical Pharmacology & Therapeutics","url":"https://doi.org/10.1016/j.clpt.2005.01.009"}]},{"name":"Cannabidiol (CBD)","kind":"botanical","role":"inhibits","potency":"moderate","mechanismBased":false,"note":"Described in vitro as a potent ATYPICAL (non-classical kinetics) CYP2D6 inhibitor; no demonstrated human CYP2D6 interaction yet.","cites":[{"key":"yamaoriSeries","text":"Yamaori S, Ebisawa J, Okushima Y, Kushihara M, Okamoto Y, Yamamoto I, Watanabe K, et al. (2011) Series of in-vitro studies characterising cannabidiol, cannabinol and Δ9-THC as isoform-selective inhibitors of human CYP1, CYP2C19, CYP2D6 and CYP3A enzymes (published 2010-2012 across Life Sciences, Biochemical Pharmacology and Drug Metabolism and Disposition) Life Sciences / Biochemical Pharmacology / Drug Metabolism and Disposition [identifier unverified]","url":""},{"key":"stout2014","text":"Stout SM, Cimino NM (2014) Exogenous cannabinoids as substrates, inhibitors, and inducers of human drug metabolizing enzymes: a systematic review Drug Metabolism Reviews","url":"https://doi.org/10.3109/03602532.2013.849268"}]},{"name":"Δ9-THC","kind":"botanical","role":"inhibits","potency":"weak","mechanismBased":false,"note":"In-vitro signal only.","cites":[{"key":"yamaoriSeries","text":"Yamaori S, Ebisawa J, Okushima Y, Kushihara M, Okamoto Y, Yamamoto I, Watanabe K, et al. (2011) Series of in-vitro studies characterising cannabidiol, cannabinol and Δ9-THC as isoform-selective inhibitors of human CYP1, CYP2C19, CYP2D6 and CYP3A enzymes (published 2010-2012 across Life Sciences, Biochemical Pharmacology and Drug Metabolism and Disposition) Life Sciences / Biochemical Pharmacology / Drug Metabolism and Disposition [identifier unverified]","url":""},{"key":"nasrin2021","text":"Nasrin S, Watson CJW, Perez-Paramo YX, Lazarus P (2021) Cannabinoid metabolites as inhibitors of major hepatic CYP450 enzymes, with implications for cannabis-drug interactions Drug Metabolism and Disposition","url":"https://doi.org/10.1124/dmd.121.000442"}]},{"name":"Curcuminoids (turmeric)","kind":"botanical","role":"inhibits","potency":"weak","mechanismBased":false,"note":"Weak in-vitro inhibition; human magnitude unestablished.","cites":[{"key":"volak2008","text":"Volak LP, Ghirmai S, Cashman JR, Court MH (2008) Curcuminoids Inhibit Multiple Human Cytochromes P450, UDP-Glucuronosyltransferase, and Sulfotransferase Enzymes, whereas Piperine is a Relatively Selective CYP3A4 Inhibitor Drug Metabolism and Disposition","url":"https://doi.org/10.1124/dmd.108.020552"}]},{"name":"Piperine (black pepper)","kind":"botanical","role":"inhibits","potency":"weak","mechanismBased":false,"note":"Characterised as relatively selective for CYP3A4, so a CYP2D6 role is weak at best.","cites":[{"key":"bhardwaj2002","text":"Bhardwaj RK, Glaeser H, Becquemont L, Klotz U, Gupta SK, Fromm MF (2002) Piperine, a Major Constituent of Black Pepper, Inhibits Human P-glycoprotein and CYP3A4 The Journal of Pharmacology and Experimental Therapeutics","url":"https://doi.org/10.1124/jpet.102.034728"},{"key":"volak2008","text":"Volak LP, Ghirmai S, Cashman JR, Court MH (2008) Curcuminoids Inhibit Multiple Human Cytochromes P450, UDP-Glucuronosyltransferase, and Sulfotransferase Enzymes, whereas Piperine is a Relatively Selective CYP3A4 Inhibitor Drug Metabolism and Disposition","url":"https://doi.org/10.1124/dmd.108.020552"}]},{"name":"Nutmeg (myristicin, elemicin, safrole)","kind":"botanical","role":"inhibits","potency":"weak","mechanismBased":false,"note":"In-vitro inhibition described; human confirmation at culinary or capsule doses absent, so magnitude unestablished.","cites":[{"key":"beyer2006","text":"Beyer J, Ehlers D, Maurer HH (2006) Abuse of Nutmeg (Myristica fragrans Houtt.): Studies on the Metabolism and the Toxicologic Detection of its Ingredients Elemicin, Myristicin, and Safrole in Rat and Human Urine Using Gas Chromatography/Mass Spectrometry Therapeutic Drug Monitoring","url":"https://doi.org/10.1097/00007691-200608000-00013"},{"key":"flockhart","text":"Flockhart DA, Thacker D, McDonald C, Desta Z (2021) The Flockhart Cytochrome P450 Drug-Drug Interaction Table Division of Clinical Pharmacology, Indiana University School of Medicine","url":"https://drug-interactions.medicine.iu.edu"}]},{"name":"Kava","kind":"botanical","role":"inhibits","potency":"unclear","mechanismBased":false,"note":"NEGATIVE finding in the in-vivo human probe study: no significant CYP2D6 inhibition. Recorded because the positive claim is common.","cites":[{"key":"gurley2005","text":"Gurley BJ, Gardner SF, Hubbard MA, et al. (2005) In vivo effects of goldenseal, kava kava, black cohosh, and valerian on human cytochrome P450 1A2, 2D6, 2E1, and 3A4/5 phenotypes Clinical Pharmacology & Therapeutics","url":"https://doi.org/10.1016/j.clpt.2005.01.009"}]},{"name":"Black cohosh","kind":"botanical","role":"inhibits","potency":"unclear","mechanismBased":false,"note":"NEGATIVE in the same in-vivo human probe study, which is worth carrying because CYP2D6 inhibition is frequently claimed for it.","cites":[{"key":"gurley2005","text":"Gurley BJ, Gardner SF, Hubbard MA, et al. (2005) In vivo effects of goldenseal, kava kava, black cohosh, and valerian on human cytochrome P450 1A2, 2D6, 2E1, and 3A4/5 phenotypes Clinical Pharmacology & Therapeutics","url":"https://doi.org/10.1016/j.clpt.2005.01.009"}]},{"name":"Valerian","kind":"botanical","role":"inhibits","potency":"unclear","mechanismBased":false,"note":"NEGATIVE in the same in-vivo human probe study.","cites":[{"key":"gurley2005","text":"Gurley BJ, Gardner SF, Hubbard MA, et al. (2005) In vivo effects of goldenseal, kava kava, black cohosh, and valerian on human cytochrome P450 1A2, 2D6, 2E1, and 3A4/5 phenotypes Clinical Pharmacology & Therapeutics","url":"https://doi.org/10.1016/j.clpt.2005.01.009"}]},{"name":"Grapefruit juice","kind":"botanical","role":"inhibits","potency":"weak","mechanismBased":false,"note":"Named explicitly: the grapefruit effect is CYP3A4 and does not transfer to CYP2D6.","cites":[{"key":"bailey2013","text":"Bailey DG, Dresser G, Arnold JMO (2013) Grapefruit–medication interactions: Forbidden fruit or avoidable consequences? CMAJ (published online 2012-11-26)","url":"https://doi.org/10.1503/cmaj.120951"}]}],"inducers":[]},{"id":"cyp1a2","name":"CYP1A2","page":"/science/cyp450/cyp1a2","substrates":[{"name":"Caffeine","nti":false,"note":"The standard CYP1A2 probe. If a new medication makes a habitual coffee feel like three, this enzyme is the reason.","cites":["culmmerdek2005","flockhart"]},{"name":"Theophylline","nti":true,"note":"Narrow margin with seizures and arrhythmia; the archetypal de-induction casualty on smoking cessation.","cites":["faber2004","flockhart"]},{"name":"Clozapine","nti":true,"note":"Levels can roughly double after smoking cessation with no dose change; toxicity includes seizures, myocarditis and profound sedation.","cites":["faber2004","flockhart"]},{"name":"Olanzapine","nti":false,"note":"Same induction relationship as clozapine with a wider margin.","cites":["faber2004","flockhart"]},{"name":"Tizanidine","nti":false,"note":"The most extreme documented CYP1A2 victim: fluvoxamine or ciprofloxacin produce very large exposure increases with severe hypotension and sedation.","cites":["flockhart","fdaTable"]},{"name":"Duloxetine","nti":false,"note":"CYP1A2 and CYP2D6 substrate.","cites":["flockhart"]},{"name":"Melatonin","nti":false,"note":"Very high first-pass extraction, so a CYP1A2 inhibitor raises exposure sharply.","cites":["flockhart"]},{"name":"Ramelteon","nti":false,"note":"Same high first-pass relationship as melatonin; contraindicated with fluvoxamine.","cites":["fdaTable"]},{"name":"R-warfarin","nti":false,"note":"The LESS potent enantiomer, which is why CYP1A2 matters much less for the INR than CYP2C9 does.","cites":["holbrook2005","flockhart"]},{"name":"Propranolol","nti":false,"note":"Partial CYP1A2 clearance.","cites":["flockhart"]},{"name":"Mexiletine","nti":false,"note":"Substrate and moderate inhibitor of the same enzyme.","cites":["flockhart"]},{"name":"Tacrine","nti":false,"note":"Historical CYP1A2 substrate with a large smoking effect.","cites":["flockhart"]},{"name":"Zolmitriptan","nti":false,"note":"CYP1A2 substrate triptan.","cites":["flockhart"]},{"name":"Agomelatine","nti":false,"note":"Contraindicated with strong CYP1A2 inhibitors.","cites":["fdaTable"]},{"name":"Oestradiol","nti":false,"note":"CYP1A2 contributes to 2-hydroxylation, which is why cruciferous vegetables and smoking appear in the oestrogen-metabolism literature.","cites":["kall1996","flockhart"]},{"name":"Heterocyclic aromatic amines from charred meat","nti":false,"note":"BIOACTIVATED by CYP1A2 rather than detoxified — the enzyme cuts both ways.","cites":["guengerich2008"]}],"inhibitors":[{"name":"Fluvoxamine","kind":"drug","role":"inhibits","potency":"strong","mechanismBased":false,"note":"Roughly fivefold reduction in caffeine clearance in volunteers, without altering caffeine pharmacodynamics — a clean demonstration that a large pharmacokinetic interaction can leave the pharmacodynamics untouched.","cites":[{"key":"culmmerdek2005","text":"Culm-Merdek KE, von Moltke LL, Harmatz JS, Greenblatt DJ (2005) Fluvoxamine impairs single-dose caffeine clearance without altering caffeine pharmacodynamics British Journal of Clinical Pharmacology","url":"https://doi.org/10.1111/j.1365-2125.2005.02467.x"},{"key":"fdaTable","text":"U.S. Food and Drug Administration (2023) Drug Development and Drug Interactions: Table of Substrates, Inhibitors and Inducers FDA","url":"https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-drug-interactions-table-substrates-inhibitors-and-inducers"}]},{"name":"Ciprofloxacin","kind":"drug","role":"inhibits","potency":"strong","mechanismBased":false,"note":"A short antibiotic course is enough; the classic accidental theophylline and clozapine toxicity.","cites":[{"key":"fdaTable","text":"U.S. Food and Drug Administration (2023) Drug Development and Drug Interactions: Table of Substrates, Inhibitors and Inducers FDA","url":"https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-drug-interactions-table-substrates-inhibitors-and-inducers"},{"key":"flockhart","text":"Flockhart DA, Thacker D, McDonald C, Desta Z (2021) The Flockhart Cytochrome P450 Drug-Drug Interaction Table Division of Clinical Pharmacology, Indiana University School of Medicine","url":"https://drug-interactions.medicine.iu.edu"}]},{"name":"Enoxacin","kind":"drug","role":"inhibits","potency":"strong","mechanismBased":false,"note":"Historically the most potent quinolone inhibitor of this enzyme.","cites":[{"key":"fdaTable","text":"U.S. Food and Drug Administration (2023) Drug Development and Drug Interactions: Table of Substrates, Inhibitors and Inducers FDA","url":"https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-drug-interactions-table-substrates-inhibitors-and-inducers"}]},{"name":"Levofloxacin","kind":"drug","role":"inhibits","potency":"weak","mechanismBased":false,"note":"Named explicitly: one of the quinolones that largely avoids the problem.","cites":[{"key":"flockhart","text":"Flockhart DA, Thacker D, McDonald C, Desta Z (2021) The Flockhart Cytochrome P450 Drug-Drug Interaction Table Division of Clinical Pharmacology, Indiana University School of Medicine","url":"https://drug-interactions.medicine.iu.edu"}]},{"name":"Moxifloxacin","kind":"drug","role":"inhibits","potency":"weak","mechanismBased":false,"note":"Named explicitly: largely avoids the CYP1A2 problem, though it carries QT risk of its own.","cites":[{"key":"flockhart","text":"Flockhart DA, Thacker D, McDonald C, Desta Z (2021) The Flockhart Cytochrome P450 Drug-Drug Interaction Table Division of Clinical Pharmacology, Indiana University School of Medicine","url":"https://drug-interactions.medicine.iu.edu"},{"key":"crediblemeds","text":"Woosley RL, Heise CW, Gallo T, Woosley RD, Lambson J, Romero KA (2025) QTdrugs List CredibleMeds, AZCERT Inc.","url":"https://crediblemeds.org"}]},{"name":"Combined oral contraceptives","kind":"drug","role":"inhibits","potency":"moderate","mechanismBased":false,"note":"Under-recognised moderate inhibition; contributes to caffeine tolerance changing with contraceptive use.","cites":[{"key":"flockhart","text":"Flockhart DA, Thacker D, McDonald C, Desta Z (2021) The Flockhart Cytochrome P450 Drug-Drug Interaction Table Division of Clinical Pharmacology, Indiana University School of Medicine","url":"https://drug-interactions.medicine.iu.edu"}]},{"name":"Cimetidine","kind":"drug","role":"inhibits","potency":"moderate","mechanismBased":false,"note":"Broad weak-to-moderate inhibition; the other H2 blockers do not share it.","cites":[{"key":"flockhart","text":"Flockhart DA, Thacker D, McDonald C, Desta Z (2021) The Flockhart Cytochrome P450 Drug-Drug Interaction Table Division of Clinical Pharmacology, Indiana University School of Medicine","url":"https://drug-interactions.medicine.iu.edu"}]},{"name":"Mexiletine","kind":"drug","role":"inhibits","potency":"moderate","mechanismBased":false,"note":"Documented moderate inhibitor and substrate.","cites":[{"key":"flockhart","text":"Flockhart DA, Thacker D, McDonald C, Desta Z (2021) The Flockhart Cytochrome P450 Drug-Drug Interaction Table Division of Clinical Pharmacology, Indiana University School of Medicine","url":"https://drug-interactions.medicine.iu.edu"}]},{"name":"Zileuton","kind":"drug","role":"inhibits","potency":"moderate","mechanismBased":false,"note":"Documented moderate inhibitor.","cites":[{"key":"fdaTable","text":"U.S. Food and Drug Administration (2023) Drug Development and Drug Interactions: Table of Substrates, Inhibitors and Inducers FDA","url":"https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-drug-interactions-table-substrates-inhibitors-and-inducers"}]},{"name":"Thiabendazole","kind":"drug","role":"inhibits","potency":"moderate","mechanismBased":false,"note":"Documented moderate inhibitor.","cites":[{"key":"flockhart","text":"Flockhart DA, Thacker D, McDonald C, Desta Z (2021) The Flockhart Cytochrome P450 Drug-Drug Interaction Table Division of Clinical Pharmacology, Indiana University School of Medicine","url":"https://drug-interactions.medicine.iu.edu"}]},{"name":"Cannabidiol (CBD)","kind":"botanical","role":"inhibits","potency":"moderate","mechanismBased":false,"note":"Described in vitro as an isoform-selective and relatively potent CYP1 inhibitor; human magnitude unquantified, and it opposes the induction from smoking the plant.","cites":[{"key":"yamaoriSeries","text":"Yamaori S, Ebisawa J, Okushima Y, Kushihara M, Okamoto Y, Yamamoto I, Watanabe K, et al. (2011) Series of in-vitro studies characterising cannabidiol, cannabinol and Δ9-THC as isoform-selective inhibitors of human CYP1, CYP2C19, CYP2D6 and CYP3A enzymes (published 2010-2012 across Life Sciences, Biochemical Pharmacology and Drug Metabolism and Disposition) Life Sciences / Biochemical Pharmacology / Drug Metabolism and Disposition [identifier unverified]","url":""},{"key":"stout2014","text":"Stout SM, Cimino NM (2014) Exogenous cannabinoids as substrates, inhibitors, and inducers of human drug metabolizing enzymes: a systematic review Drug Metabolism Reviews","url":"https://doi.org/10.3109/03602532.2013.849268"}]},{"name":"Cannabinol (CBN)","kind":"botanical","role":"inhibits","potency":"moderate","mechanismBased":false,"note":"Among the more potent CYP1 inhibitors in the same in-vitro series.","cites":[{"key":"yamaoriSeries","text":"Yamaori S, Ebisawa J, Okushima Y, Kushihara M, Okamoto Y, Yamamoto I, Watanabe K, et al. (2011) Series of in-vitro studies characterising cannabidiol, cannabinol and Δ9-THC as isoform-selective inhibitors of human CYP1, CYP2C19, CYP2D6 and CYP3A enzymes (published 2010-2012 across Life Sciences, Biochemical Pharmacology and Drug Metabolism and Disposition) Life Sciences / Biochemical Pharmacology / Drug Metabolism and Disposition [identifier unverified]","url":""},{"key":"stout2014","text":"Stout SM, Cimino NM (2014) Exogenous cannabinoids as substrates, inhibitors, and inducers of human drug metabolizing enzymes: a systematic review Drug Metabolism Reviews","url":"https://doi.org/10.3109/03602532.2013.849268"}]},{"name":"Curcuminoids (turmeric)","kind":"botanical","role":"inhibits","potency":"moderate","mechanismBased":false,"note":"In-vitro inhibition across several isoforms including this one.","cites":[{"key":"volak2008","text":"Volak LP, Ghirmai S, Cashman JR, Court MH (2008) Curcuminoids Inhibit Multiple Human Cytochromes P450, UDP-Glucuronosyltransferase, and Sulfotransferase Enzymes, whereas Piperine is a Relatively Selective CYP3A4 Inhibitor Drug Metabolism and Disposition","url":"https://doi.org/10.1124/dmd.108.020552"},{"key":"bahramsoltani2017","text":"Bahramsoltani R, Rahimi R, Farzaei MH (2017) Pharmacokinetic interactions of curcuminoids with conventional drugs: A review Journal of Ethnopharmacology","url":"https://doi.org/10.1016/j.jep.2017.07.022"}]},{"name":"Piperine (black pepper)","kind":"botanical","role":"inhibits","potency":"weak","mechanismBased":false,"note":"Claimed as a CYP1A2 inhibitor in the operator corpus; the controlled selectivity comparison favours CYP3A4, so low confidence.","cites":[{"key":"bhardwaj2002","text":"Bhardwaj RK, Glaeser H, Becquemont L, Klotz U, Gupta SK, Fromm MF (2002) Piperine, a Major Constituent of Black Pepper, Inhibits Human P-glycoprotein and CYP3A4 The Journal of Pharmacology and Experimental Therapeutics","url":"https://doi.org/10.1124/jpet.102.034728"},{"key":"volak2008","text":"Volak LP, Ghirmai S, Cashman JR, Court MH (2008) Curcuminoids Inhibit Multiple Human Cytochromes P450, UDP-Glucuronosyltransferase, and Sulfotransferase Enzymes, whereas Piperine is a Relatively Selective CYP3A4 Inhibitor Drug Metabolism and Disposition","url":"https://doi.org/10.1124/dmd.108.020552"},{"key":"kavaDatasheet2026","text":"Van Kush Family Research Institute (Temple Pharmacopoeia Project) (2026) Kava Potentiators Datasheet, reconstructed from the 2020 KavaForums potentiators thread Operator corpus, MELEK knowledge base [identifier unverified]","url":""}]},{"name":"Chamomile","kind":"botanical","role":"inhibits","potency":"weak","mechanismBased":false,"note":"In-vitro flavonoid (apigenin) inhibition without established human relevance at dietary intake.","cites":[{"key":"flockhart","text":"Flockhart DA, Thacker D, McDonald C, Desta Z (2021) The Flockhart Cytochrome P450 Drug-Drug Interaction Table Division of Clinical Pharmacology, Indiana University School of Medicine","url":"https://drug-interactions.medicine.iu.edu"}]},{"name":"Peppermint","kind":"botanical","role":"inhibits","potency":"weak","mechanismBased":false,"note":"In-vitro signal only.","cites":[{"key":"flockhart","text":"Flockhart DA, Thacker D, McDonald C, Desta Z (2021) The Flockhart Cytochrome P450 Drug-Drug Interaction Table Division of Clinical Pharmacology, Indiana University School of Medicine","url":"https://drug-interactions.medicine.iu.edu"}]},{"name":"Grapefruit juice (naringenin)","kind":"botanical","role":"inhibits","potency":"weak","mechanismBased":false,"note":"Weak flavonoid inhibition; the grapefruit story is CYP3A4, not this isoform.","cites":[{"key":"bailey2013","text":"Bailey DG, Dresser G, Arnold JMO (2013) Grapefruit–medication interactions: Forbidden fruit or avoidable consequences? CMAJ (published online 2012-11-26)","url":"https://doi.org/10.1503/cmaj.120951"}]},{"name":"Kava","kind":"botanical","role":"inhibits","potency":"unclear","mechanismBased":false,"note":"NEGATIVE in the in-vivo human probe study: no significant CYP1A2 change.","cites":[{"key":"gurley2005","text":"Gurley BJ, Gardner SF, Hubbard MA, et al. (2005) In vivo effects of goldenseal, kava kava, black cohosh, and valerian on human cytochrome P450 1A2, 2D6, 2E1, and 3A4/5 phenotypes Clinical Pharmacology & Therapeutics","url":"https://doi.org/10.1016/j.clpt.2005.01.009"}]},{"name":"Black cohosh","kind":"botanical","role":"inhibits","potency":"unclear","mechanismBased":false,"note":"NEGATIVE in the same in-vivo human probe study.","cites":[{"key":"gurley2005","text":"Gurley BJ, Gardner SF, Hubbard MA, et al. (2005) In vivo effects of goldenseal, kava kava, black cohosh, and valerian on human cytochrome P450 1A2, 2D6, 2E1, and 3A4/5 phenotypes Clinical Pharmacology & Therapeutics","url":"https://doi.org/10.1016/j.clpt.2005.01.009"}]},{"name":"Valerian","kind":"botanical","role":"inhibits","potency":"unclear","mechanismBased":false,"note":"NEGATIVE in the same in-vivo human probe study.","cites":[{"key":"gurley2005","text":"Gurley BJ, Gardner SF, Hubbard MA, et al. (2005) In vivo effects of goldenseal, kava kava, black cohosh, and valerian on human cytochrome P450 1A2, 2D6, 2E1, and 3A4/5 phenotypes Clinical Pharmacology & Therapeutics","url":"https://doi.org/10.1016/j.clpt.2005.01.009"}]},{"name":"Goldenseal","kind":"botanical","role":"inhibits","potency":"unclear","mechanismBased":false,"note":"No significant CYP1A2 change in the in-vivo human probe study, despite its clear CYP2D6 and CYP3A4 effects.","cites":[{"key":"gurley2005","text":"Gurley BJ, Gardner SF, Hubbard MA, et al. (2005) In vivo effects of goldenseal, kava kava, black cohosh, and valerian on human cytochrome P450 1A2, 2D6, 2E1, and 3A4/5 phenotypes Clinical Pharmacology & Therapeutics","url":"https://doi.org/10.1016/j.clpt.2005.01.009"}]}],"inducers":[{"name":"Tobacco smoke (polycyclic aromatic hydrocarbons)","kind":"lifestyle","role":"induces","potency":"strong","mechanismBased":false,"note":"AhR-mediated. The inducer is the SMOKE, not the nicotine, so patches, gum and vapes do not maintain it. Activity falls by about 36 percent within roughly a week of cessation, and clozapine levels can roughly double — a documented cause of toxicity on smoke-free admission.","cites":[{"key":"faber2004","text":"Faber MS, Fuhr U (2004) Time response of cytochrome P450 1A2 activity on cessation of heavy smoking Clinical Pharmacology & Therapeutics","url":"https://doi.org/10.1016/j.clpt.2004.04.003"},{"key":"flockhart","text":"Flockhart DA, Thacker D, McDonald C, Desta Z (2021) The Flockhart Cytochrome P450 Drug-Drug Interaction Table Division of Clinical Pharmacology, Indiana University School of Medicine","url":"https://drug-interactions.medicine.iu.edu"}]},{"name":"Cannabis smoke","kind":"lifestyle","role":"induces","potency":"moderate","mechanismBased":false,"note":"Combustion products, not cannabinoids: smoked cannabis induces CYP1A2 by the same AhR route as tobacco, and it therefore opposes the in-vitro CYP1 inhibition of the cannabinoids themselves. The net direction in a real user is not predictable from this table.","cites":[{"key":"anderson2016","text":"Anderson GD, Chan LN (2016) Pharmacokinetic drug interactions with tobacco, cannabinoids and smoking cessation products Clinical Pharmacokinetics","url":"https://doi.org/10.1007/s40262-016-0400-9"}]},{"name":"Cruciferous vegetables (broccoli, Brussels sprouts, cabbage, kale)","kind":"food","role":"induces","potency":"moderate","mechanismBased":false,"note":"Glucosinolate breakdown products including indole-3-carbinol are AhR ligands. Real but smaller and far more variable than the smoking effect; a sustained dietary change is required for it to matter.","cites":[{"key":"kall1996","text":"Kall MA, Vang O, Clausen J (1996) Effects of dietary broccoli on human in vivo drug metabolizing enzymes: evaluation of caffeine, oestrone and chlorzoxazone metabolism Carcinogenesis","url":"https://doi.org/10.1093/carcin/17.4.793"}]},{"name":"Charbroiled or grilled meat","kind":"food","role":"induces","potency":"weak","mechanismBased":false,"note":"Same polycyclic aromatic hydrocarbon chemistry as smoke at much lower exposure.","cites":[{"key":"flockhart","text":"Flockhart DA, Thacker D, McDonald C, Desta Z (2021) The Flockhart Cytochrome P450 Drug-Drug Interaction Table Division of Clinical Pharmacology, Indiana University School of Medicine","url":"https://drug-interactions.medicine.iu.edu"},{"key":"guengerich2008","text":"Guengerich FP (2008) Cytochrome P450 and Chemical Toxicology Chemical Research in Toxicology","url":"https://doi.org/10.1021/tx700079z"}]},{"name":"Omeprazole","kind":"drug","role":"induces","potency":"moderate","mechanismBased":false,"note":"An AhR-mediated induction unrelated to its acid suppression, and often missed.","cites":[{"key":"flockhart","text":"Flockhart DA, Thacker D, McDonald C, Desta Z (2021) The Flockhart Cytochrome P450 Drug-Drug Interaction Table Division of Clinical Pharmacology, Indiana University School of Medicine","url":"https://drug-interactions.medicine.iu.edu"}]},{"name":"Rifampicin","kind":"drug","role":"induces","potency":"moderate","mechanismBased":false,"note":"Broad induction reaching this isoform.","cites":[{"key":"fdaTable","text":"U.S. Food and Drug Administration (2023) Drug Development and Drug Interactions: Table of Substrates, Inhibitors and Inducers FDA","url":"https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-drug-interactions-table-substrates-inhibitors-and-inducers"}]},{"name":"Carbamazepine","kind":"drug","role":"induces","potency":"moderate","mechanismBased":false,"note":"Broad anticonvulsant induction.","cites":[{"key":"fdaTable","text":"U.S. Food and Drug Administration (2023) Drug Development and Drug Interactions: Table of Substrates, Inhibitors and Inducers FDA","url":"https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-drug-interactions-table-substrates-inhibitors-and-inducers"},{"key":"flockhart","text":"Flockhart DA, Thacker D, McDonald C, Desta Z (2021) The Flockhart Cytochrome P450 Drug-Drug Interaction Table Division of Clinical Pharmacology, Indiana University School of Medicine","url":"https://drug-interactions.medicine.iu.edu"}]},{"name":"Phenytoin","kind":"drug","role":"induces","potency":"moderate","mechanismBased":false,"note":"Broad anticonvulsant induction.","cites":[{"key":"flockhart","text":"Flockhart DA, Thacker D, McDonald C, Desta Z (2021) The Flockhart Cytochrome P450 Drug-Drug Interaction Table Division of Clinical Pharmacology, Indiana University School of Medicine","url":"https://drug-interactions.medicine.iu.edu"}]},{"name":"Phenobarbital","kind":"drug","role":"induces","potency":"moderate","mechanismBased":false,"note":"Broad anticonvulsant induction.","cites":[{"key":"fdaTable","text":"U.S. Food and Drug Administration (2023) Drug Development and Drug Interactions: Table of Substrates, Inhibitors and Inducers FDA","url":"https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-drug-interactions-table-substrates-inhibitors-and-inducers"}]}]},{"id":"cyp2e1","name":"CYP2E1","page":"/science/cyp450/cyp2e1","substrates":[{"name":"Ethanol","nti":false,"note":"A substrate at higher concentrations (the microsomal ethanol oxidising system) as well as an inhibitor and an inducer of the same enzyme.","cites":["lieber2004"]},{"name":"Paracetamol (acetaminophen)","nti":true,"note":"CYP2E1 generates the reactive quinone imine NAPQI, detoxified by glutathione until glutathione runs out. This is the mechanism of paracetamol hepatotoxicity.","cites":["slattery1996","chien1997"]},{"name":"Chlorzoxazone","nti":false,"note":"The standard in-vivo CYP2E1 probe substrate.","cites":["gurley2005","chien1997"]},{"name":"Halothane","nti":true,"note":"CYP2E1-mediated reactive metabolite formation; halothane hepatitis is the classic case.","cites":["guengerich2008"]},{"name":"Enflurane","nti":false,"note":"CYP2E1-mediated defluorination.","cites":["guengerich2008"]},{"name":"Isoflurane","nti":false,"note":"CYP2E1-mediated defluorination.","cites":["guengerich2008"]},{"name":"Sevoflurane","nti":false,"note":"CYP2E1-mediated defluorination.","cites":["guengerich2008"]},{"name":"Benzene","nti":false,"note":"Bioactivated rather than detoxified; the occupational-toxicology side of this enzyme.","cites":["guengerich2008"]},{"name":"Carbon tetrachloride","nti":false,"note":"Bioactivated to a hepatotoxic radical.","cites":["guengerich2008"]},{"name":"Vinyl chloride","nti":false,"note":"Bioactivated; occupational carcinogen.","cites":["guengerich2008"]},{"name":"Styrene","nti":false,"note":"Occupational solvent substrate.","cites":["guengerich2008"]},{"name":"Trichloroethylene","nti":false,"note":"Substrate and inducer.","cites":["guengerich2008"]},{"name":"N-nitrosodimethylamine and related nitrosamines","nti":false,"note":"Bioactivation; part of why CYP2E1 appears in cancer epidemiology.","cites":["guengerich2008"]},{"name":"Isoniazid","nti":false,"note":"Substrate, inhibitor while present, and inducer once cleared — all three in one drug.","cites":["zand1993","chien1997"]},{"name":"Theophylline","nti":true,"note":"Minor contribution compared with CYP1A2.","cites":["flockhart"]}],"inhibitors":[{"name":"Disulfiram","kind":"drug","role":"inhibits","potency":"strong","mechanismBased":true,"note":"Mechanism-based inactivation after metabolism to diethyldithiocarbamate; the reference CYP2E1 inhibitor in probe studies.","cites":[{"key":"chien1997","text":"Chien JY, Thummel KE, Slattery JT (1997) Pharmacokinetic consequences of induction of CYP2E1 by ligand stabilization Drug Metabolism and Disposition [identifier unverified]","url":""},{"key":"flockhart","text":"Flockhart DA, Thacker D, McDonald C, Desta Z (2021) The Flockhart Cytochrome P450 Drug-Drug Interaction Table Division of Clinical Pharmacology, Indiana University School of Medicine","url":"https://drug-interactions.medicine.iu.edu"}]},{"name":"Ethanol (acute, while present)","kind":"lifestyle","role":"inhibits","potency":"moderate","mechanismBased":false,"note":"Competitive inhibition at the active site — which is why acute intoxication transiently PROTECTS against paracetamol bioactivation, the opposite of the widely repeated claim.","cites":[{"key":"slattery1996","text":"Slattery JT, Nelson SD, Thummel KE (1996) The complex interaction between ethanol and acetaminophen Clinical Pharmacology & Therapeutics","url":"https://doi.org/10.1016/s0009-9236(96)90050-8"},{"key":"lieber2004","text":"Lieber CS (2004) The discovery of the microsomal ethanol oxidizing system and its physiologic and pathologic role Drug Metabolism Reviews","url":"https://doi.org/10.1081/dmr-200033441"}]},{"name":"Isoniazid (while present)","kind":"drug","role":"inhibits","potency":"moderate","mechanismBased":false,"note":"Inhibits while circulating, then induces once cleared — the direction flips within a dosing interval.","cites":[{"key":"zand1993","text":"Zand R, Nelson SD, Slattery JT, et al. (1993) Inhibition and induction of cytochrome P4502E1-catalyzed oxidation by isoniazid in humans Clinical Pharmacology & Therapeutics","url":"https://doi.org/10.1038/clpt.1993.125"},{"key":"chien1997","text":"Chien JY, Thummel KE, Slattery JT (1997) Pharmacokinetic consequences of induction of CYP2E1 by ligand stabilization Drug Metabolism and Disposition [identifier unverified]","url":""}]},{"name":"Kava","kind":"botanical","role":"inhibits","potency":"moderate","mechanismBased":false,"note":"Roughly 40 percent inhibition of CYP2E1 in a 28-day in-vivo human probe study — the best-evidenced botanical CYP effect for kava, and NOT the isoform the potentiation corpus emphasises.","cites":[{"key":"gurley2005","text":"Gurley BJ, Gardner SF, Hubbard MA, et al. (2005) In vivo effects of goldenseal, kava kava, black cohosh, and valerian on human cytochrome P450 1A2, 2D6, 2E1, and 3A4/5 phenotypes Clinical Pharmacology & Therapeutics","url":"https://doi.org/10.1016/j.clpt.2005.01.009"},{"key":"kavaDatasheet2026","text":"Van Kush Family Research Institute (Temple Pharmacopoeia Project) (2026) Kava Potentiators Datasheet, reconstructed from the 2020 KavaForums potentiators thread Operator corpus, MELEK knowledge base [identifier unverified]","url":""}]},{"name":"Watercress (phenethyl isothiocyanate)","kind":"food","role":"inhibits","potency":"moderate","mechanismBased":false,"note":"Human probe-study signal; the best-documented dietary CYP2E1 inhibitor.","cites":[{"key":"kall1996","text":"Kall MA, Vang O, Clausen J (1996) Effects of dietary broccoli on human in vivo drug metabolizing enzymes: evaluation of caffeine, oestrone and chlorzoxazone metabolism Carcinogenesis","url":"https://doi.org/10.1093/carcin/17.4.793"},{"key":"chien1997","text":"Chien JY, Thummel KE, Slattery JT (1997) Pharmacokinetic consequences of induction of CYP2E1 by ligand stabilization Drug Metabolism and Disposition [identifier unverified]","url":""}]},{"name":"Garlic (diallyl sulfide and related organosulfur compounds)","kind":"botanical","role":"inhibits","potency":"weak","mechanismBased":false,"note":"Animal and in-vitro data are consistent; controlled human magnitude is less clear.","cites":[{"key":"kavaDatasheet2026","text":"Van Kush Family Research Institute (Temple Pharmacopoeia Project) (2026) Kava Potentiators Datasheet, reconstructed from the 2020 KavaForums potentiators thread Operator corpus, MELEK knowledge base [identifier unverified]","url":""},{"key":"gurley2005","text":"Gurley BJ, Gardner SF, Hubbard MA, et al. (2005) In vivo effects of goldenseal, kava kava, black cohosh, and valerian on human cytochrome P450 1A2, 2D6, 2E1, and 3A4/5 phenotypes Clinical Pharmacology & Therapeutics","url":"https://doi.org/10.1016/j.clpt.2005.01.009"}]},{"name":"Cruciferous vegetables (isothiocyanates)","kind":"food","role":"inhibits","potency":"weak","mechanismBased":false,"note":"Dietary intervention signal, small and variable — and note the same vegetables INDUCE CYP1A2.","cites":[{"key":"kall1996","text":"Kall MA, Vang O, Clausen J (1996) Effects of dietary broccoli on human in vivo drug metabolizing enzymes: evaluation of caffeine, oestrone and chlorzoxazone metabolism Carcinogenesis","url":"https://doi.org/10.1093/carcin/17.4.793"}]},{"name":"Black cohosh","kind":"botanical","role":"inhibits","potency":"unclear","mechanismBased":false,"note":"NEGATIVE for CYP2E1 in the in-vivo human probe study.","cites":[{"key":"gurley2005","text":"Gurley BJ, Gardner SF, Hubbard MA, et al. (2005) In vivo effects of goldenseal, kava kava, black cohosh, and valerian on human cytochrome P450 1A2, 2D6, 2E1, and 3A4/5 phenotypes Clinical Pharmacology & Therapeutics","url":"https://doi.org/10.1016/j.clpt.2005.01.009"}]},{"name":"Valerian","kind":"botanical","role":"inhibits","potency":"unclear","mechanismBased":false,"note":"NEGATIVE for CYP2E1 in the same study.","cites":[{"key":"gurley2005","text":"Gurley BJ, Gardner SF, Hubbard MA, et al. (2005) In vivo effects of goldenseal, kava kava, black cohosh, and valerian on human cytochrome P450 1A2, 2D6, 2E1, and 3A4/5 phenotypes Clinical Pharmacology & Therapeutics","url":"https://doi.org/10.1016/j.clpt.2005.01.009"}]},{"name":"Goldenseal","kind":"botanical","role":"inhibits","potency":"unclear","mechanismBased":false,"note":"NEGATIVE for CYP2E1 in the same study, despite its CYP2D6 and CYP3A4 effects.","cites":[{"key":"gurley2005","text":"Gurley BJ, Gardner SF, Hubbard MA, et al. (2005) In vivo effects of goldenseal, kava kava, black cohosh, and valerian on human cytochrome P450 1A2, 2D6, 2E1, and 3A4/5 phenotypes Clinical Pharmacology & Therapeutics","url":"https://doi.org/10.1016/j.clpt.2005.01.009"}]}],"inducers":[{"name":"Ethanol (chronic heavy use)","kind":"lifestyle","role":"induces","potency":"strong","mechanismBased":false,"note":"Substrate-mediated protein stabilisation rather than transcription alone. Chronic use induces, which is the paracetamol risk factor; acute presence inhibits. The two statements are not contradictory.","cites":[{"key":"lieber2004","text":"Lieber CS (2004) The discovery of the microsomal ethanol oxidizing system and its physiologic and pathologic role Drug Metabolism Reviews","url":"https://doi.org/10.1081/dmr-200033441"},{"key":"slattery1996","text":"Slattery JT, Nelson SD, Thummel KE (1996) The complex interaction between ethanol and acetaminophen Clinical Pharmacology & Therapeutics","url":"https://doi.org/10.1016/s0009-9236(96)90050-8"}]},{"name":"Isoniazid (after clearance)","kind":"drug","role":"induces","potency":"moderate","mechanismBased":false,"note":"The same stabilisation mechanism; documented to raise paracetamol bioactivation.","cites":[{"key":"zand1993","text":"Zand R, Nelson SD, Slattery JT, et al. (1993) Inhibition and induction of cytochrome P4502E1-catalyzed oxidation by isoniazid in humans Clinical Pharmacology & Therapeutics","url":"https://doi.org/10.1038/clpt.1993.125"},{"key":"chien1997","text":"Chien JY, Thummel KE, Slattery JT (1997) Pharmacokinetic consequences of induction of CYP2E1 by ligand stabilization Drug Metabolism and Disposition [identifier unverified]","url":""}]},{"name":"Fasting, ketosis, prolonged low-carbohydrate intake","kind":"lifestyle","role":"induces","potency":"moderate","mechanismBased":false,"note":"Acetone and other ketones stabilise the enzyme. A physiological state acting as an inducer, with no drug involved — and it coincides with glutathione depletion, which is why the two risk factors arrive together.","cites":[{"key":"chien1997","text":"Chien JY, Thummel KE, Slattery JT (1997) Pharmacokinetic consequences of induction of CYP2E1 by ligand stabilization Drug Metabolism and Disposition [identifier unverified]","url":""},{"key":"slattery1996","text":"Slattery JT, Nelson SD, Thummel KE (1996) The complex interaction between ethanol and acetaminophen Clinical Pharmacology & Therapeutics","url":"https://doi.org/10.1016/s0009-9236(96)90050-8"}]},{"name":"Obesity, insulin resistance, type 2 diabetes, non-alcoholic fatty liver","kind":"lifestyle","role":"induces","potency":"moderate","mechanismBased":false,"note":"Elevated CYP2E1 expression is a documented feature of these states.","cites":[{"key":"leung2012","text":"Leung T, Rajendran R, Singh S, Garva R, Krstic-Demonacos M, Demonacos C (2012) Cytochrome P450 2E1 (CYP2E1) regulates the response to oxidative stress and migration of breast cancer cells Breast Cancer Research","url":"https://doi.org/10.1186/bcr3574"},{"key":"lieber2004","text":"Lieber CS (2004) The discovery of the microsomal ethanol oxidizing system and its physiologic and pathologic role Drug Metabolism Reviews","url":"https://doi.org/10.1081/dmr-200033441"}]},{"name":"Acetone","kind":"lifestyle","role":"induces","potency":"variable","mechanismBased":false,"note":"Ligand stabilisation; the mechanistic link between ketosis and induction.","cites":[{"key":"chien1997","text":"Chien JY, Thummel KE, Slattery JT (1997) Pharmacokinetic consequences of induction of CYP2E1 by ligand stabilization Drug Metabolism and Disposition [identifier unverified]","url":""}]},{"name":"Pyridine","kind":"lifestyle","role":"induces","potency":"variable","mechanismBased":false,"note":"Occupational exposure acting by the same stabilisation route.","cites":[{"key":"chien1997","text":"Chien JY, Thummel KE, Slattery JT (1997) Pharmacokinetic consequences of induction of CYP2E1 by ligand stabilization Drug Metabolism and Disposition [identifier unverified]","url":""}]},{"name":"Trichloroethylene","kind":"lifestyle","role":"induces","potency":"variable","mechanismBased":false,"note":"Occupational solvent that is both substrate and inducer.","cites":[{"key":"guengerich2008","text":"Guengerich FP (2008) Cytochrome P450 and Chemical Toxicology Chemical Research in Toxicology","url":"https://doi.org/10.1021/tx700079z"}]}]},{"id":"ugt","name":"UGT glucuronidation (UGT1A1, 1A4, 1A9, 2B7)","page":"/science/cyp450/ugt","substrates":[{"name":"Bilirubin (UGT1A1)","nti":false,"note":"The endogenous marker substrate. Reduced UGT1A1 function is Gilbert syndrome; complete deficiency is Crigler-Najjar syndrome.","cites":["rowland2013","innocenti2004"]},{"name":"SN-38, the active metabolite of irinotecan (UGT1A1)","nti":true,"note":"UGT1A1 star-28 and star-6 reduced-function genotypes slow SN-38 inactivation and predict severe neutropenia and diarrhoea; genotype information is on the label.","cites":["innocenti2004","ando2000"]},{"name":"Lamotrigine (UGT1A4)","nti":false,"note":"Valproate roughly doubles its exposure; carbamazepine, phenytoin, phenobarbital and ethinylestradiol roughly halve it. Rash risk is tied to escalation speed, which makes this a safety interaction.","cites":["anderson1996","rowland2013"]},{"name":"Morphine (UGT2B7)","nti":false,"note":"Conjugated to morphine-3-glucuronide and morphine-6-glucuronide; M6G is itself an active opioid, so this conjugation is not simply inactivation.","cites":["rowland2013","clarke1994"]},{"name":"Valproate (UGT2B7)","nti":false,"note":"Substrate and inhibitor within the same pathway.","cites":["anderson1996","rowland2013"]},{"name":"Mycophenolic acid (UGT1A9)","nti":true,"note":"Transplant exposure turns on this isoform; rifampicin induction lowers it.","cites":["rowland2013"]},{"name":"Propofol (UGT1A9)","nti":false,"note":"Major UGT1A9 substrate.","cites":["rowland2013"]},{"name":"Zidovudine (UGT2B7)","nti":false,"note":"Glucuronidation is its principal clearance route.","cites":["rowland2013"]},{"name":"Lorazepam, oxazepam, temazepam","nti":false,"note":"Directly glucuronidated rather than oxidised, which is why they largely escape CYP interactions and are preferred in liver impairment and polypharmacy.","cites":["flockhart","rowland2013"]},{"name":"11-nor-9-carboxy-THC (THC-COOH)","nti":false,"note":"Glucuronidated principally by UGT1A9, with UGT1A3 and UGT2B7 contributions. THC-COOH-glucuronide is the dominant urinary species and the analyte behind a urine cannabinoid screen; confirmatory chromatography hydrolyses it first, which is why free and total carboxy-THC are different numbers.","cites":["mazur2009","scheidweiler2013","huestis2007"]},{"name":"11-hydroxy-THC","nti":false,"note":"The psychoactive phase-1 metabolite formed mainly by CYP2C9; oral dosing generates far more of it than inhalation, which explains most of the difference between an edible and an inhaled dose.","cites":["huestis2007","sachseseeboth2009"]},{"name":"Cannabidiol","nti":false,"note":"Glucuronidated by UGT1A9, UGT2B7 and UGT2B17, and a direct substrate as a phenol as well as after oxidation.","cites":["mazur2009","jiang2011"]},{"name":"Clozapine, olanzapine (UGT1A4)","nti":true,"note":"N-glucuronidation contributes to their clearance alongside CYP1A2.","cites":["rowland2013","flockhart"]},{"name":"Amitriptyline, imipramine, trifluoperazine (UGT1A4)","nti":true,"note":"Quaternary N-glucuronides, an unusual conjugate type specific to UGT1A4.","cites":["rowland2013"]},{"name":"NSAIDs (UGT2B7)","nti":false,"note":"Acyl glucuronides of carboxylic acids are chemically reactive and are implicated in idiosyncratic toxicity — a conjugate that is not simply inert.","cites":["rowland2013","clarke1994"]}],"inhibitors":[{"name":"Valproate","kind":"drug","role":"inhibits","potency":"moderate","mechanismBased":false,"note":"The best-documented UGT drug interaction in clinical use: inhibits UGT1A4 and roughly doubles lamotrigine exposure and half-life, so lamotrigine starting doses and escalation steps are halved.","cites":[{"key":"anderson1996","text":"Anderson GD, Yau MK, Gidal BE, et al. (1996) Bidirectional interaction of valproate and lamotrigine in healthy subjects Clinical Pharmacology & Therapeutics","url":"https://doi.org/10.1016/s0009-9236(96)90130-7"},{"key":"rowland2013","text":"Rowland A, Miners JO, Mackenzie PI (2013) The UDP-glucuronosyltransferases: their role in drug metabolism and detoxification The International Journal of Biochemistry & Cell Biology","url":"https://doi.org/10.1016/j.biocel.2013.02.019"}]},{"name":"Cannabidiol (CBD)","kind":"botanical","role":"inhibits","potency":"moderate","mechanismBased":false,"note":"Inhibits UGT1A9 and UGT2B7 in vitro. UGT2B7 is the morphine enzyme and UGT1A9 handles mycophenolate and propofol, which is why this matters — and it has never been followed up with a controlled human study.","cites":[{"key":"mazur2009","text":"Mazur A, Lichti CF, Prather PL, et al. (2009) Characterization of human hepatic and extrahepatic UDP-glucuronosyltransferase enzymes involved in the metabolism of classic cannabinoids Drug Metabolism and Disposition","url":"https://doi.org/10.1124/dmd.109.026898"},{"key":"jiang2011","text":"Jiang R, Yamaori S, Takeda S, Yamamoto I, Watanabe K (2011) Identification of cytochrome P450 enzymes responsible for metabolism of cannabidiol by human liver microsomes Life Sciences","url":"https://doi.org/10.1016/j.lfs.2011.05.018"},{"key":"nasrin2021","text":"Nasrin S, Watson CJW, Perez-Paramo YX, Lazarus P (2021) Cannabinoid metabolites as inhibitors of major hepatic CYP450 enzymes, with implications for cannabis-drug interactions Drug Metabolism and Disposition","url":"https://doi.org/10.1124/dmd.121.000442"},{"key":"stout2014","text":"Stout SM, Cimino NM (2014) Exogenous cannabinoids as substrates, inhibitors, and inducers of human drug metabolizing enzymes: a systematic review Drug Metabolism Reviews","url":"https://doi.org/10.3109/03602532.2013.849268"}]},{"name":"Curcuminoids (turmeric)","kind":"botanical","role":"inhibits","potency":"moderate","mechanismBased":false,"note":"Inhibits UGT and SULT as well as multiple CYPs — phase 1 and both phase-2 pathways from one botanical.","cites":[{"key":"volak2008","text":"Volak LP, Ghirmai S, Cashman JR, Court MH (2008) Curcuminoids Inhibit Multiple Human Cytochromes P450, UDP-Glucuronosyltransferase, and Sulfotransferase Enzymes, whereas Piperine is a Relatively Selective CYP3A4 Inhibitor Drug Metabolism and Disposition","url":"https://doi.org/10.1124/dmd.108.020552"},{"key":"bahramsoltani2017","text":"Bahramsoltani R, Rahimi R, Farzaei MH (2017) Pharmacokinetic interactions of curcuminoids with conventional drugs: A review Journal of Ethnopharmacology","url":"https://doi.org/10.1016/j.jep.2017.07.022"}]},{"name":"Probenecid","kind":"drug","role":"inhibits","potency":"moderate","mechanismBased":false,"note":"The classical UGT inhibitor, used deliberately to raise exposure of glucuronidated drugs.","cites":[{"key":"rowland2013","text":"Rowland A, Miners JO, Mackenzie PI (2013) The UDP-glucuronosyltransferases: their role in drug metabolism and detoxification The International Journal of Biochemistry & Cell Biology","url":"https://doi.org/10.1016/j.biocel.2013.02.019"}]},{"name":"Atazanavir","kind":"drug","role":"inhibits","potency":"moderate","mechanismBased":false,"note":"Inhibits UGT1A1, causing benign unconjugated hyperbilirubinaemia — a visible, harmless marker of a real UGT interaction.","cites":[{"key":"rowland2013","text":"Rowland A, Miners JO, Mackenzie PI (2013) The UDP-glucuronosyltransferases: their role in drug metabolism and detoxification The International Journal of Biochemistry & Cell Biology","url":"https://doi.org/10.1016/j.biocel.2013.02.019"}]},{"name":"Indinavir","kind":"drug","role":"inhibits","potency":"moderate","mechanismBased":false,"note":"Same UGT1A1 inhibition and hyperbilirubinaemia signal.","cites":[{"key":"rowland2013","text":"Rowland A, Miners JO, Mackenzie PI (2013) The UDP-glucuronosyltransferases: their role in drug metabolism and detoxification The International Journal of Biochemistry & Cell Biology","url":"https://doi.org/10.1016/j.biocel.2013.02.019"}]},{"name":"Fluconazole","kind":"drug","role":"inhibits","potency":"weak","mechanismBased":false,"note":"Some UGT inhibition on top of its CYP effects.","cites":[{"key":"rowland2013","text":"Rowland A, Miners JO, Mackenzie PI (2013) The UDP-glucuronosyltransferases: their role in drug metabolism and detoxification The International Journal of Biochemistry & Cell Biology","url":"https://doi.org/10.1016/j.biocel.2013.02.019"}]},{"name":"Ketoconazole","kind":"drug","role":"inhibits","potency":"weak","mechanismBased":false,"note":"Some UGT inhibition on top of its CYP effects.","cites":[{"key":"rowland2013","text":"Rowland A, Miners JO, Mackenzie PI (2013) The UDP-glucuronosyltransferases: their role in drug metabolism and detoxification The International Journal of Biochemistry & Cell Biology","url":"https://doi.org/10.1016/j.biocel.2013.02.019"}]}],"inducers":[{"name":"Rifampicin","kind":"drug","role":"induces","potency":"strong","mechanismBased":false,"note":"Induces UGT1A1, UGT1A4 and UGT2B7 as well as CYP and P-glycoprotein — which is why it lowers lamotrigine and mycophenolate exposure.","cites":[{"key":"rowland2013","text":"Rowland A, Miners JO, Mackenzie PI (2013) The UDP-glucuronosyltransferases: their role in drug metabolism and detoxification The International Journal of Biochemistry & Cell Biology","url":"https://doi.org/10.1016/j.biocel.2013.02.019"},{"key":"fdaTable","text":"U.S. Food and Drug Administration (2023) Drug Development and Drug Interactions: Table of Substrates, Inhibitors and Inducers FDA","url":"https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-drug-interactions-table-substrates-inhibitors-and-inducers"}]},{"name":"Carbamazepine","kind":"drug","role":"induces","potency":"moderate","mechanismBased":false,"note":"Roughly halves lamotrigine exposure, the mirror image of the valproate interaction.","cites":[{"key":"anderson1996","text":"Anderson GD, Yau MK, Gidal BE, et al. (1996) Bidirectional interaction of valproate and lamotrigine in healthy subjects Clinical Pharmacology & Therapeutics","url":"https://doi.org/10.1016/s0009-9236(96)90130-7"},{"key":"rowland2013","text":"Rowland A, Miners JO, Mackenzie PI (2013) The UDP-glucuronosyltransferases: their role in drug metabolism and detoxification The International Journal of Biochemistry & Cell Biology","url":"https://doi.org/10.1016/j.biocel.2013.02.019"}]},{"name":"Phenytoin","kind":"drug","role":"induces","potency":"moderate","mechanismBased":false,"note":"Roughly halves lamotrigine exposure.","cites":[{"key":"anderson1996","text":"Anderson GD, Yau MK, Gidal BE, et al. (1996) Bidirectional interaction of valproate and lamotrigine in healthy subjects Clinical Pharmacology & Therapeutics","url":"https://doi.org/10.1016/s0009-9236(96)90130-7"}]},{"name":"Phenobarbital","kind":"drug","role":"induces","potency":"moderate","mechanismBased":false,"note":"Roughly halves lamotrigine exposure.","cites":[{"key":"anderson1996","text":"Anderson GD, Yau MK, Gidal BE, et al. (1996) Bidirectional interaction of valproate and lamotrigine in healthy subjects Clinical Pharmacology & Therapeutics","url":"https://doi.org/10.1016/s0009-9236(96)90130-7"}]},{"name":"Combined oral contraceptives (ethinylestradiol)","kind":"drug","role":"induces","potency":"moderate","mechanismBased":false,"note":"Induce UGT1A4 and roughly halve lamotrigine concentrations; levels rise again in the pill-free week and on stopping, making it a cyclical interaction that can produce toxicity with no dose change.","cites":[{"key":"anderson1996","text":"Anderson GD, Yau MK, Gidal BE, et al. (1996) Bidirectional interaction of valproate and lamotrigine in healthy subjects Clinical Pharmacology & Therapeutics","url":"https://doi.org/10.1016/s0009-9236(96)90130-7"},{"key":"rowland2013","text":"Rowland A, Miners JO, Mackenzie PI (2013) The UDP-glucuronosyltransferases: their role in drug metabolism and detoxification The International Journal of Biochemistry & Cell Biology","url":"https://doi.org/10.1016/j.biocel.2013.02.019"}]},{"name":"St John's wort","kind":"botanical","role":"induces","potency":"weak","mechanismBased":false,"note":"UGT induction via PXR, part of the same programme as its CYP3A4 and P-glycoprotein effect.","cites":[{"key":"moore2000","text":"Moore LB, Goodwin B, Jones SA, et al. (2000) St. John's wort induces hepatic drug metabolism through activation of the pregnane X receptor PNAS","url":"https://doi.org/10.1073/pnas.130155097"}]},{"name":"Tobacco smoke","kind":"lifestyle","role":"induces","potency":"weak","mechanismBased":false,"note":"AhR-mediated UGT1A1 and UGT1A9 induction accompanies the better-known CYP1A2 induction.","cites":[{"key":"anderson2016","text":"Anderson GD, Chan LN (2016) Pharmacokinetic drug interactions with tobacco, cannabinoids and smoking cessation products Clinical Pharmacokinetics","url":"https://doi.org/10.1007/s40262-016-0400-9"}]}]},{"id":"sult","name":"SULT sulfonation (SULT1A1, 1A3)","page":"/science/cyp450/sult","substrates":[{"name":"Paracetamol (acetaminophen)","nti":true,"note":"Sulfation carries a substantial fraction at therapeutic doses and SATURATES FIRST as the dose rises, shifting proportionally more of the dose toward glucuronidation and toward CYP2E1 oxidation to NAPQI.","cites":["koster1981","slattery1996"]},{"name":"4-nitrophenol","nti":false,"note":"The standard SULT1A1 probe substrate.","cites":["coughtrie2016","riches2009"]},{"name":"Minoxidil","nti":false,"note":"Requires SULT1A1 sulfonation to its active form — a prodrug on a phase-2 enzyme, which inverts the direction of any inhibition.","cites":["coughtrie2016"]},{"name":"Dopamine and noradrenaline (SULT1A3)","nti":false,"note":"Most circulating dopamine is sulfated, and intestinal SULT1A3 is a first-pass barrier for phenolic amines — which is part of why many orally taken monoamines never reach the circulation.","cites":["coughtrie2016","riches2009"]},{"name":"Salbutamol (SULT1A3)","nti":false,"note":"Phenolic amine sulfated in the gut wall on first pass.","cites":["coughtrie2016"]},{"name":"Oestradiol (SULT1E1 at low concentration, SULT1A1 higher)","nti":false,"note":"High-affinity oestrogen sulfotransferase contributes to local oestrogen inactivation.","cites":["coughtrie2016","riches2009"]},{"name":"DHEA and bile acids (SULT2A1)","nti":false,"note":"The adrenal and hepatic hydroxysteroid sulfotransferase.","cites":["coughtrie2016"]},{"name":"Thyroid hormones (SULT1B1)","nti":false,"note":"Contributes to thyroid hormone handling.","cites":["coughtrie2016"]},{"name":"Dietary polyphenols (flavonoids, catechins, quercetin, resveratrol, curcuminoids)","nti":false,"note":"Both substrates and competitors: a phenol-rich botanical competes for the same limited pathway as anything else phenolic present at that moment.","cites":["koster1981","volak2008","coughtrie2016"]},{"name":"1'-hydroxysafrole and the 1'-hydroxy metabolites of myristicin and elemicin","nti":false,"note":"BIOACTIVATION, not detoxification: sulfonation gives a 1-prime-sulfooxy ester that ionises to a DNA-binding electrophile. Impaired sulfation (brachymorphic mice, sulfotransferase inhibition) markedly reduces the carcinogenicity, which is the evidence that this conjugate is the hazard. Described as metabolic fate only — no preparation, dosing or combination guidance is given or implied.","cites":["jeurissen2004","boberg1983","beyer2006"]}],"inhibitors":[{"name":"Curcuminoids (turmeric)","kind":"botanical","role":"inhibits","potency":"moderate","mechanismBased":false,"note":"Inhibits sulfotransferase activity alongside UGT and multiple CYPs. Clinical consequence depends entirely on achieved systemic curcuminoid concentration, which differs by orders of magnitude between culinary turmeric and a bioavailability-enhanced formulation — and the enhanced formulations are the ones most likely to interact.","cites":[{"key":"volak2008","text":"Volak LP, Ghirmai S, Cashman JR, Court MH (2008) Curcuminoids Inhibit Multiple Human Cytochromes P450, UDP-Glucuronosyltransferase, and Sulfotransferase Enzymes, whereas Piperine is a Relatively Selective CYP3A4 Inhibitor Drug Metabolism and Disposition","url":"https://doi.org/10.1124/dmd.108.020552"},{"key":"bahramsoltani2017","text":"Bahramsoltani R, Rahimi R, Farzaei MH (2017) Pharmacokinetic interactions of curcuminoids with conventional drugs: A review Journal of Ethnopharmacology","url":"https://doi.org/10.1016/j.jep.2017.07.022"},{"key":"shoba1998","text":"Shoba G, Joy D, Joseph T, Majeed M, Rajendran R, Srinivas PSSR (1998) Influence of Piperine on the Pharmacokinetics of Curcumin in Animals and Human Volunteers Planta Medica","url":"https://doi.org/10.1055/s-2006-957450"}]},{"name":"Dietary polyphenol load (competitive sulfation and PAPS depletion)","kind":"food","role":"inhibits","potency":"variable","mechanismBased":false,"note":"Not classical inhibition: a large phenolic load occupies the enzyme and consumes the cofactor, shifting a co-administered phenol away from sulfation and toward glucuronidation and oxidation. Direction is predictable, magnitude for any specific pairing is unmeasured in humans, and dietary sulfate and sulfur-amino-acid supply are upstream determinants a table of inhibitors cannot capture.","cites":[{"key":"koster1981","text":"Koster H, Halsema I, Scholtens E, Knippers M, Mulder GJ (1981) Dose-dependent shifts in the sulfation and glucuronidation of phenolic compounds in the rat in vivo and in isolated hepatocytes: the role of saturation of phenolsulfotransferase Biochemical Pharmacology [identifier unverified]","url":""},{"key":"coughtrie2016","text":"Coughtrie MWH (2016) Function and organization of the human cytosolic sulfotransferase (SULT) family Chemico-Biological Interactions","url":"https://doi.org/10.1016/j.cbi.2016.05.005"},{"key":"riches2009","text":"Riches Z, Stanley EL, Bloomer JC, Coughtrie MWH (2009) Quantitative evaluation of the expression and activity of five major sulfotransferases (SULTs) in human tissues: the SULT pie Drug Metabolism and Disposition","url":"https://doi.org/10.1124/dmd.109.028399"}]},{"name":"Green tea catechins","kind":"botanical","role":"inhibits","potency":"weak","mechanismBased":false,"note":"Phenolic substrate and competitor at SULT1A1.","cites":[{"key":"koster1981","text":"Koster H, Halsema I, Scholtens E, Knippers M, Mulder GJ (1981) Dose-dependent shifts in the sulfation and glucuronidation of phenolic compounds in the rat in vivo and in isolated hepatocytes: the role of saturation of phenolsulfotransferase Biochemical Pharmacology [identifier unverified]","url":""},{"key":"coughtrie2016","text":"Coughtrie MWH (2016) Function and organization of the human cytosolic sulfotransferase (SULT) family Chemico-Biological Interactions","url":"https://doi.org/10.1016/j.cbi.2016.05.005"}]},{"name":"Quercetin","kind":"botanical","role":"inhibits","potency":"weak","mechanismBased":false,"note":"Phenolic substrate and competitor at SULT1A1.","cites":[{"key":"coughtrie2016","text":"Coughtrie MWH (2016) Function and organization of the human cytosolic sulfotransferase (SULT) family Chemico-Biological Interactions","url":"https://doi.org/10.1016/j.cbi.2016.05.005"}]},{"name":"Resveratrol","kind":"botanical","role":"inhibits","potency":"weak","mechanismBased":false,"note":"Phenolic substrate and competitor at SULT1A1.","cites":[{"key":"coughtrie2016","text":"Coughtrie MWH (2016) Function and organization of the human cytosolic sulfotransferase (SULT) family Chemico-Biological Interactions","url":"https://doi.org/10.1016/j.cbi.2016.05.005"}]}],"inducers":[]},{"id":"pgp","name":"P-glycoprotein (ABCB1)","page":"/science/cyp450/p-glycoprotein","substrates":[{"name":"Digoxin","nti":true,"note":"The clinical index substrate: a good P-glycoprotein substrate, negligibly CYP metabolised so a change is attributable to transport, and narrow enough in margin to be clinically visible. Also more toxic at an unchanged level when serum potassium falls.","cites":["greiner1999","johne1999","fdaTable"]},{"name":"Loperamide","nti":false,"note":"The BLOOD-BRAIN-BARRIER case: a potent opioid agonist that is peripherally restricted only because P-glycoprotein excludes it from the brain. Pump inhibition has been shown to unmask central opioid effects.","cites":["sadeque2000","schinkel1996"]},{"name":"Dabigatran etexilate","nti":false,"note":"A pure P-glycoprotein interaction with no CYP component, so it isolates the mechanism — and there is no routine monitoring assay to warn anyone.","cites":["fdaTable"]},{"name":"Apixaban","nti":false,"note":"P-glycoprotein and CYP3A4 substrate; dual inhibition raises bleeding risk substantially.","cites":["fdaTable"]},{"name":"Rivaroxaban","nti":false,"note":"P-glycoprotein and CYP3A4 substrate.","cites":["fdaTable"]},{"name":"Edoxaban","nti":false,"note":"P-glycoprotein substrate with label-specified dose reduction for inhibitors.","cites":["fdaTable"]},{"name":"Ciclosporin","nti":true,"note":"Substrate of P-glycoprotein and CYP3A4 at once — the archetype of the overlap. Also an inhibitor of both.","cites":["fdaTable","ruschitzka2000"]},{"name":"Tacrolimus","nti":true,"note":"Dual P-glycoprotein and CYP3A4 substrate with a very narrow window.","cites":["fdaTable","kuehl2001"]},{"name":"Fexofenadine","nti":false,"note":"Probe substrate — but also an OATP substrate, which is why fruit juices LOWER rather than raise its exposure. A useful warning that transporters can point in opposite directions.","cites":["bailey2013","fdaTable"]},{"name":"Colchicine","nti":true,"note":"Dual CYP3A4 and P-glycoprotein inhibition has caused fatal colchicine toxicity from simultaneous loss of both clearance routes.","cites":["fdaTable","flockhart"]},{"name":"HIV protease inhibitors","nti":false,"note":"Substrates as well as inhibitors; brain penetration is relevant to central viral reservoirs.","cites":["fdaTable","piscitelli2000"]},{"name":"Kinase inhibitors, anthracyclines, vinca alkaloids, taxanes","nti":true,"note":"P-glycoprotein overexpression in tumour cells is the original multidrug-resistance phenotype the protein was named for.","cites":["schinkel2003","fdaTable"]},{"name":"Quinidine","nti":true,"note":"Substrate AND inhibitor — the same molecule on both sides of the table.","cites":["sadeque2000","fdaTable"]},{"name":"Verapamil","nti":false,"note":"Substrate and the classical inhibitor.","cites":["wandel2002","fdaTable"]},{"name":"Amiodarone","nti":true,"note":"Substrate and inhibitor with a half-life in weeks.","cites":["fdaTable"]},{"name":"Δ9-THC, cannabidiol, cannabinol","nti":false,"note":"Reported as inhibitors more than as efficiently transported substrates; the cannabinoid relationship with this transporter is less clean than with the CYPs.","cites":["zhu2006","stout2014"]}],"inhibitors":[{"name":"Verapamil","kind":"drug","role":"inhibits","potency":"moderate","mechanismBased":false,"note":"The classical P-glycoprotein inhibitor; also a CYP3A4 inhibitor.","cites":[{"key":"wandel2002","text":"Wandel C, Kim RB, Kajiji S, Guengerich FP, Wilkinson GR, Wood AJJ (2002) P-glycoprotein and cytochrome P-450 3A inhibition: dissociation of inhibitory potencies Cancer Research [identifier unverified]","url":""},{"key":"fdaTable","text":"U.S. Food and Drug Administration (2023) Drug Development and Drug Interactions: Table of Substrates, Inhibitors and Inducers FDA","url":"https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-drug-interactions-table-substrates-inhibitors-and-inducers"}]},{"name":"Ritonavir","kind":"drug","role":"inhibits","potency":"strong","mechanismBased":false,"note":"Strong on both P-glycoprotein and CYP3A4 — the reason it works as a booster.","cites":[{"key":"fdaTable","text":"U.S. Food and Drug Administration (2023) Drug Development and Drug Interactions: Table of Substrates, Inhibitors and Inducers FDA","url":"https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-drug-interactions-table-substrates-inhibitors-and-inducers"}]},{"name":"Clarithromycin","kind":"drug","role":"inhibits","potency":"strong","mechanismBased":false,"note":"Dual mechanism; a recognised cause of digoxin and colchicine toxicity.","cites":[{"key":"fdaTable","text":"U.S. Food and Drug Administration (2023) Drug Development and Drug Interactions: Table of Substrates, Inhibitors and Inducers FDA","url":"https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-drug-interactions-table-substrates-inhibitors-and-inducers"},{"key":"flockhart","text":"Flockhart DA, Thacker D, McDonald C, Desta Z (2021) The Flockhart Cytochrome P450 Drug-Drug Interaction Table Division of Clinical Pharmacology, Indiana University School of Medicine","url":"https://drug-interactions.medicine.iu.edu"}]},{"name":"Quinidine","kind":"drug","role":"inhibits","potency":"strong","mechanismBased":false,"note":"The agent used experimentally to demonstrate increased brain delivery by P-glycoprotein inhibition.","cites":[{"key":"sadeque2000","text":"Sadeque AJM, Wandel C, He H, Shah S, Wood AJJ (2000) Increased drug delivery to the brain by P-glycoprotein inhibition Clinical Pharmacology & Therapeutics","url":"https://doi.org/10.1067/mcp.2000.109156"},{"key":"fdaTable","text":"U.S. Food and Drug Administration (2023) Drug Development and Drug Interactions: Table of Substrates, Inhibitors and Inducers FDA","url":"https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-drug-interactions-table-substrates-inhibitors-and-inducers"}]},{"name":"Amiodarone","kind":"drug","role":"inhibits","potency":"moderate","mechanismBased":false,"note":"Long half-life; classic digoxin interaction.","cites":[{"key":"fdaTable","text":"U.S. Food and Drug Administration (2023) Drug Development and Drug Interactions: Table of Substrates, Inhibitors and Inducers FDA","url":"https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-drug-interactions-table-substrates-inhibitors-and-inducers"}]},{"name":"Dronedarone","kind":"drug","role":"inhibits","potency":"moderate","mechanismBased":false,"note":"Same class effect as amiodarone with a shorter half-life.","cites":[{"key":"fdaTable","text":"U.S. Food and Drug Administration (2023) Drug Development and Drug Interactions: Table of Substrates, Inhibitors and Inducers FDA","url":"https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-drug-interactions-table-substrates-inhibitors-and-inducers"}]},{"name":"Ciclosporin","kind":"drug","role":"inhibits","potency":"moderate","mechanismBased":false,"note":"Dual CYP3A4 and P-glycoprotein inhibitor as well as a substrate of both.","cites":[{"key":"fdaTable","text":"U.S. Food and Drug Administration (2023) Drug Development and Drug Interactions: Table of Substrates, Inhibitors and Inducers FDA","url":"https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-drug-interactions-table-substrates-inhibitors-and-inducers"}]},{"name":"Itraconazole","kind":"drug","role":"inhibits","potency":"moderate","mechanismBased":false,"note":"Dual CYP3A4 and P-glycoprotein inhibitor.","cites":[{"key":"fdaTable","text":"U.S. Food and Drug Administration (2023) Drug Development and Drug Interactions: Table of Substrates, Inhibitors and Inducers FDA","url":"https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-drug-interactions-table-substrates-inhibitors-and-inducers"}]},{"name":"Ketoconazole","kind":"drug","role":"inhibits","potency":"moderate","mechanismBased":false,"note":"Dual inhibitor — but note that in-vitro P-glycoprotein and CYP3A4 inhibitory potencies do not track each other even for agents that do both.","cites":[{"key":"wandel2002","text":"Wandel C, Kim RB, Kajiji S, Guengerich FP, Wilkinson GR, Wood AJJ (2002) P-glycoprotein and cytochrome P-450 3A inhibition: dissociation of inhibitory potencies Cancer Research [identifier unverified]","url":""},{"key":"fdaTable","text":"U.S. Food and Drug Administration (2023) Drug Development and Drug Interactions: Table of Substrates, Inhibitors and Inducers FDA","url":"https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-drug-interactions-table-substrates-inhibitors-and-inducers"}]},{"name":"Grapefruit juice","kind":"botanical","role":"inhibits","potency":"weak","mechanismBased":false,"note":"A WEAK P-glycoprotein inhibitor. Its clinical reputation rests on CYP3A4, and for fexofenadine it actually LOWERS exposure by inhibiting OATP uptake — the opposite direction.","cites":[{"key":"bailey2013","text":"Bailey DG, Dresser G, Arnold JMO (2013) Grapefruit–medication interactions: Forbidden fruit or avoidable consequences? CMAJ (published online 2012-11-26)","url":"https://doi.org/10.1503/cmaj.120951"}]},{"name":"Piperine (black pepper)","kind":"botanical","role":"inhibits","potency":"moderate","mechanismBased":false,"note":"Inhibits P-glycoprotein AND CYP3A4 — the mechanistic basis of its bioavailability-enhancer reputation, and why the measured effect on curcumin bioavailability was roughly twentyfold rather than modest.","cites":[{"key":"bhardwaj2002","text":"Bhardwaj RK, Glaeser H, Becquemont L, Klotz U, Gupta SK, Fromm MF (2002) Piperine, a Major Constituent of Black Pepper, Inhibits Human P-glycoprotein and CYP3A4 The Journal of Pharmacology and Experimental Therapeutics","url":"https://doi.org/10.1124/jpet.102.034728"},{"key":"shoba1998","text":"Shoba G, Joy D, Joseph T, Majeed M, Rajendran R, Srinivas PSSR (1998) Influence of Piperine on the Pharmacokinetics of Curcumin in Animals and Human Volunteers Planta Medica","url":"https://doi.org/10.1055/s-2006-957450"}]},{"name":"Curcumin (turmeric)","kind":"botanical","role":"inhibits","potency":"moderate","mechanismBased":false,"note":"P-glycoprotein inhibition alongside its CYP, UGT and SULT effects.","cites":[{"key":"volak2008","text":"Volak LP, Ghirmai S, Cashman JR, Court MH (2008) Curcuminoids Inhibit Multiple Human Cytochromes P450, UDP-Glucuronosyltransferase, and Sulfotransferase Enzymes, whereas Piperine is a Relatively Selective CYP3A4 Inhibitor Drug Metabolism and Disposition","url":"https://doi.org/10.1124/dmd.108.020552"},{"key":"bahramsoltani2017","text":"Bahramsoltani R, Rahimi R, Farzaei MH (2017) Pharmacokinetic interactions of curcuminoids with conventional drugs: A review Journal of Ethnopharmacology","url":"https://doi.org/10.1016/j.jep.2017.07.022"}]},{"name":"Quercetin","kind":"botanical","role":"inhibits","potency":"weak","mechanismBased":false,"note":"Flavonoid P-glycoprotein inhibition, well described in vitro and poorly quantified in humans.","cites":[{"key":"flockhart","text":"Flockhart DA, Thacker D, McDonald C, Desta Z (2021) The Flockhart Cytochrome P450 Drug-Drug Interaction Table Division of Clinical Pharmacology, Indiana University School of Medicine","url":"https://drug-interactions.medicine.iu.edu"}]},{"name":"Naringenin","kind":"botanical","role":"inhibits","potency":"weak","mechanismBased":false,"note":"Citrus flavonoid; in-vitro inhibition without established human magnitude.","cites":[{"key":"bailey2013","text":"Bailey DG, Dresser G, Arnold JMO (2013) Grapefruit–medication interactions: Forbidden fruit or avoidable consequences? CMAJ (published online 2012-11-26)","url":"https://doi.org/10.1503/cmaj.120951"}]},{"name":"Silymarin (milk thistle)","kind":"botanical","role":"inhibits","potency":"weak","mechanismBased":false,"note":"In-vitro inhibition; human studies have generally been negative or small.","cites":[{"key":"flockhart","text":"Flockhart DA, Thacker D, McDonald C, Desta Z (2021) The Flockhart Cytochrome P450 Drug-Drug Interaction Table Division of Clinical Pharmacology, Indiana University School of Medicine","url":"https://drug-interactions.medicine.iu.edu"}]},{"name":"Green tea catechins","kind":"botanical","role":"inhibits","potency":"weak","mechanismBased":false,"note":"In-vitro inhibition; human magnitude unestablished.","cites":[{"key":"flockhart","text":"Flockhart DA, Thacker D, McDonald C, Desta Z (2021) The Flockhart Cytochrome P450 Drug-Drug Interaction Table Division of Clinical Pharmacology, Indiana University School of Medicine","url":"https://drug-interactions.medicine.iu.edu"}]},{"name":"Δ9-THC","kind":"botanical","role":"inhibits","potency":"weak","mechanismBased":false,"note":"Characterised as a P-glycoprotein inhibitor in vitro; clinical magnitude unestablished.","cites":[{"key":"zhu2006","text":"Zhu HJ, Wang JS, Markowitz JS, et al. (2006) Characterization of P-glycoprotein inhibition by major cannabinoids from marijuana The Journal of Pharmacology and Experimental Therapeutics","url":"https://doi.org/10.1124/jpet.105.098541"},{"key":"stout2014","text":"Stout SM, Cimino NM (2014) Exogenous cannabinoids as substrates, inhibitors, and inducers of human drug metabolizing enzymes: a systematic review Drug Metabolism Reviews","url":"https://doi.org/10.3109/03602532.2013.849268"}]},{"name":"Cannabidiol (CBD)","kind":"botanical","role":"inhibits","potency":"weak","mechanismBased":false,"note":"Characterised as a P-glycoprotein inhibitor in vitro; clinical magnitude unestablished.","cites":[{"key":"zhu2006","text":"Zhu HJ, Wang JS, Markowitz JS, et al. (2006) Characterization of P-glycoprotein inhibition by major cannabinoids from marijuana The Journal of Pharmacology and Experimental Therapeutics","url":"https://doi.org/10.1124/jpet.105.098541"},{"key":"stout2014","text":"Stout SM, Cimino NM (2014) Exogenous cannabinoids as substrates, inhibitors, and inducers of human drug metabolizing enzymes: a systematic review Drug Metabolism Reviews","url":"https://doi.org/10.3109/03602532.2013.849268"}]},{"name":"Cannabinol (CBN)","kind":"botanical","role":"inhibits","potency":"weak","mechanismBased":false,"note":"Same in-vitro cannabinoid series.","cites":[{"key":"zhu2006","text":"Zhu HJ, Wang JS, Markowitz JS, et al. (2006) Characterization of P-glycoprotein inhibition by major cannabinoids from marijuana The Journal of Pharmacology and Experimental Therapeutics","url":"https://doi.org/10.1124/jpet.105.098541"}]}],"inducers":[{"name":"Rifampicin","kind":"drug","role":"induces","potency":"strong","mechanismBased":false,"note":"Intestinal P-glycoprotein induction was demonstrated directly as the mechanism of its digoxin interaction — one of the cleanest transporter-induction results in human pharmacology.","cites":[{"key":"greiner1999","text":"Greiner B, Eichelbaum M, Fritz P, et al. (1999) The role of intestinal P-glycoprotein in the interaction of digoxin and rifampin Journal of Clinical Investigation","url":"https://doi.org/10.1172/jci6663"},{"key":"fdaTable","text":"U.S. Food and Drug Administration (2023) Drug Development and Drug Interactions: Table of Substrates, Inhibitors and Inducers FDA","url":"https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-drug-interactions-table-substrates-inhibitors-and-inducers"}]},{"name":"St John's wort (hyperforin)","kind":"botanical","role":"induces","potency":"strong","mechanismBased":false,"note":"PXR-mediated induction of ABCB1 and CYP3A4 together — two mechanisms pointing the same way on an overlapping substrate set. Reduced digoxin exposure was measured with a hypericum extract.","cites":[{"key":"johne1999","text":"Johne A, Brockmöller J, Bauer S, Maurer A, Langheinrich M, Roots I (1999) Pharmacokinetic interaction of digoxin with an herbal extract from St John's wort (Hypericum perforatum) Clinical Pharmacology & Therapeutics","url":"https://doi.org/10.1053/cp.1999.v66.a101944"},{"key":"moore2000","text":"Moore LB, Goodwin B, Jones SA, et al. (2000) St. John's wort induces hepatic drug metabolism through activation of the pregnane X receptor PNAS","url":"https://doi.org/10.1073/pnas.130155097"},{"key":"henderson2002","text":"Henderson L, Yue QY, Bergquist C, Gerden B, Arlett P (2002) St John's wort (Hypericum perforatum): drug interactions and clinical outcomes British Journal of Clinical Pharmacology","url":"https://doi.org/10.1046/j.1365-2125.2002.01683.x"}]},{"name":"Carbamazepine","kind":"drug","role":"induces","potency":"moderate","mechanismBased":false,"note":"Broad PXR and CAR induction reaching ABCB1.","cites":[{"key":"fdaTable","text":"U.S. Food and Drug Administration (2023) Drug Development and Drug Interactions: Table of Substrates, Inhibitors and Inducers FDA","url":"https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-drug-interactions-table-substrates-inhibitors-and-inducers"}]},{"name":"Phenytoin","kind":"drug","role":"induces","potency":"moderate","mechanismBased":false,"note":"Broad induction reaching ABCB1.","cites":[{"key":"fdaTable","text":"U.S. Food and Drug Administration (2023) Drug Development and Drug Interactions: Table of Substrates, Inhibitors and Inducers FDA","url":"https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-drug-interactions-table-substrates-inhibitors-and-inducers"}]},{"name":"Ritonavir (chronic dosing)","kind":"drug","role":"induces","potency":"moderate","mechanismBased":false,"note":"Inhibits acutely and induces on chronic dosing — the direction depends on the timescale.","cites":[{"key":"fdaTable","text":"U.S. Food and Drug Administration (2023) Drug Development and Drug Interactions: Table of Substrates, Inhibitors and Inducers FDA","url":"https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-drug-interactions-table-substrates-inhibitors-and-inducers"}]},{"name":"Tobacco smoke","kind":"lifestyle","role":"induces","potency":"weak","mechanismBased":false,"note":"Weak and inconsistent ABCB1 signal, unlike its strong CYP1A2 effect.","cites":[{"key":"anderson2016","text":"Anderson GD, Chan LN (2016) Pharmacokinetic drug interactions with tobacco, cannabinoids and smoking cessation products Clinical Pharmacokinetics","url":"https://doi.org/10.1007/s40262-016-0400-9"}]}]}]}