CYP2C19

What it metabolises human data

CYP2C19 carries a smaller share of overall drug metabolism than CYP3A4 or CYP2C9 but a disproportionate share of the clinically actionable pharmacogenetics, because several of its substrates are either prodrugs or drugs with a narrow tolerability window. The proton pump inhibitors are its signature substrates, which produces a second-order effect worth noticing: omeprazole and esomeprazole are both substrates and inhibitors of the enzyme that clears them, so they inhibit their own metabolism and that of other CYP2C19 substrates, while pantoprazole and rabeprazole depend on it less. For this library the important entries are cannabidiol, which is oxidised principally by CYP2C19 and CYP3A4, and clobazam, whose N-desmethyl metabolite is cleared by CYP2C19 and accumulates when the enzyme is inhibited.

Sources: Flockhart DA 2021 · U.S. Food 2023 · Desta Z 2002 · Mega JL 2009 · Geffrey AL 2015 · Morrison G 2019 · Jiang R 2011 · Woosley RL 2025

Drug inhibitors and inducers, with FDA potency classes human data

Same definitions throughout this shelf: strong inhibitor raises a sensitive index substrate AUC five-fold or more, moderate at least two-fold and under five-fold, weak at least 1.25-fold and under two-fold. CYP2C19 is unusual in having several strong inhibitors that are widely prescribed, and one — fluvoxamine — that is also the strongest common CYP1A2 inhibitor, so a single tablet perturbs two axes at once.

Sources: U.S. Food 2023 · U.S. Food 2020* · Flockhart DA 2021 · Desta Z 2002 · Mega JL 2009

Botanical and cannabinoid inhibitors: the CBD and clobazam case contested human data

This is the best-documented cannabinoid drug interaction in the clinical literature, and it is worth walking through because it is the model for how a cannabinoid interaction is properly established. Clobazam is a benzodiazepine whose parent compound is cleared by CYP3A4 and whose principal active metabolite, N-desmethylclobazam (norclobazam), is cleared by CYP2C19. In children with refractory epilepsy given cannabidiol alongside clobazam, N-desmethylclobazam concentrations rose several-fold — on the order of a threefold to fivefold increase in the original paediatric series — while parent clobazam moved much less, and the clinical correlate was sedation, requiring clobazam dose reduction in a majority of the children. A subsequent formal phase-1 drug-interaction study in healthy volunteers reproduced the effect on N-desmethylclobazam. Two features make this case instructive. First, the interaction is on the METABOLITE, so anyone watching only the parent drug concentration would have concluded nothing was happening. Second, part of the observed seizure benefit attributed to cannabidiol in early clobazam-co-treated cohorts is confounded by this pharmacokinetic boost — the drug interaction was doing some of the work that was initially credited to the cannabinoid, which is a reminder that a pharmacokinetic interaction can masquerade as efficacy. Cannabidiol also raises exposure to the active metabolite of stiripentol and interacts with valproate, although the valproate signal in the trials was hepatic transaminase elevation rather than a clean pharmacokinetic change.

Contested — caveat. The cannabidiol and clobazam interaction is solidly established at pharmaceutical cannabidiol doses (hundreds of milligrams per day, weight-based) and should NOT be extrapolated unchanged to a low-dose consumer CBD product, where systemic exposure is orders of magnitude lower and the effect has not been measured. The kava, turmeric and Δ9-THC entries on this isoform are in-vitro signals without human confirmation.

Sources: Geffrey AL 2015 · Morrison G 2019 · Jiang R 2011 · Yamaori S 2011* · Stout SM 2014 · Nasrin S 2021 · Mathews JM 2002 · Zou L 2002 · Gurley BJ 2005 · Volak LP 2008 · Moore LB 2000 · Van Kush Family Research Institute (Temple Pharmacopoeia Project) 2026*

Clinical consequence, concretely human data

Clopidogrel plus a CYP2C19 inhibitor, or clopidogrel in a poor metaboliser, produces nothing the patient can feel — and then a stent thrombosis, a myocardial infarction or a stroke. That silence is the whole problem, and it is why the clopidogrel label carries a boxed warning about diminished effectiveness in poor metabolisers and why prasugrel and ticagrelor, which do not depend on CYP2C19, are preferred when genotype or interaction makes clopidogrel unreliable. Clobazam plus cannabidiol produces sedation, somnolence and ataxia in a child whose anticonvulsant dose has not been changed. Diazepam in a poor metaboliser, or with an inhibitor, produces prolonged sedation because nordiazepam has a half-life of days. Voriconazole exposure swings in both directions on genotype: an ultra-rapid or increased-function phenotype underexposes and the fungal infection progresses, while a poor metaboliser accumulates and develops visual disturbance, hallucinations and hepatotoxicity — which is why voriconazole is one of the drugs most often managed by measured plasma concentrations rather than by dose alone.

Sources: Mega JL 2009 · Desta Z 2002 · Geffrey AL 2015 · Morrison G 2019 · Flockhart DA 2021

Polymorphism contested human data

CYP2C19 star-2 (a splice-site variant) and star-3 (a premature stop codon) are the common loss-of-function alleles, and their combined frequency produces a poor-metaboliser phenotype in roughly 2 to 5 percent of people of European ancestry and, in the frequently cited literature, 15 to 25 percent of people of East and South-East Asian ancestry. The star-17 promoter variant increases transcription and produces a rapid or ultra-rapid phenotype. The consequences run in both directions depending on whether the substrate is a drug or a prodrug, and the clopidogrel case is the reason this enzyme has an FDA boxed warning at all: a poor metaboliser forms less active thiol metabolite, gets less platelet inhibition, and has measurably worse cardiovascular outcomes on clopidogrel after percutaneous coronary intervention. A rapid metaboliser has the mirror problem with escitalopram or a PPI — subtherapeutic exposure at a standard dose. Because an inhibitor converts a normal metaboliser into a functional poor metaboliser, genotype and interaction are not separate questions; they add.

• Star-2 and star-3: loss of function. Star-17: increased function.
• Poor-metaboliser frequency varies several-fold between populations, but the crude continental groupings used in the older literature are a poor guide for any individual.
• Prodrug direction: poor metaboliser equals treatment failure (clopidogrel, proguanil).
• Ordinary substrate direction: poor metaboliser equals accumulation (diazepam, citalopram, voriconazole).
• Phenoconversion: a strong inhibitor makes a normal metaboliser behave like a poor one, so genotype-guided prescribing has to account for the rest of the medication list.

Contested — caveat. Population frequency figures are drawn from the older pharmacogenetic literature and are reported by broad ancestral grouping, which does not predict an individual. Randomised trials of genotype-guided antiplatelet selection have been more equivocal than the pharmacokinetic and observational data, so the mechanism is solid while the clinical utility of routine genotyping remains debated.

Sources: Desta Z 2002 · Mega JL 2009 · Zanger UM 2013 · Flockhart DA 2021