[4,8,12,13] Six major classes of CYP isoenzymes that play a vital role in drug biotransformation are CYP 1A2, CYP 2C19, CYP 2C9, CYP 2D6, CYP 2E1, and CYP 3A4.
Genetic polymorphism is common with CYP 2C19 and CYP 2D6 isoenzymes.
PPIs competitively inhibit CYP 2C19 and CYP 3A4 enzymes responsible for the biotransformation of clopidogrel to an active drug, leading to loss of antiplatelet activity.
The medication is metabolized primarily by oxidation through cytochrome P (CYP) 450: CYP2D6 (primary), CYP 3A4/5, CYP 2C19
, CYP 2C9, CYP2A6, CYP2C8, and CYP2B6 with subsequent glucuronidation.
However, at least for clopidogrel as a CYP 2C19
substrate, patients who are carriers for *2 or *3 have higher incidence of adverse cardiac events after percutaneous coronary angioplasty; therefore, they should not be listed as EMs.
(55, 56) CYP 2C19
phenotypes are reported to affect clinical benefit of several drugs, such as proton pump inhibitors, clopitogrel, sertraline, escitalopram, moclobemide and voriconazol.
* The maximum recommended dose for patients with hepatic impairment, who are older than 60 years, who are CYP 2C19
poor metabolizers, or who are taking cimetidine is 20 mg/day because each of these factors can increase blood levels of citalopram, thus increasing the risk of QT interval prolongation and torsades de points.
(17) Clopidogrel's antiplatelet effect, however, is highly dependent on specific cytochrome P-450 (CYP) enzymes for conversion to its active metabolite, and can be impaired by genetic variations in CYP 2C19
, as well as by medication interactions.
All PPIs except rabeprazole are metabolized by the P450 system enzyme CYP 2C19
. The bioavailability of omeprazole and esomeprazole increases after the first week of dosage due to a progressive reduction in their hepatic clearance.
Five distinct human cytochromes mediate amitriptyline N-demethylation in vitro: dominance of CYP 2C19
Fluoxetine, fluvoxamine, and paroxetine are the SSRIs with the greatest likelihood of having a significant CYP 450 interaction by inhibiting the metabolism of medications mediated by CYP 2D6, CYP 1A2, and CYP 2C19
. (9,10) (A partial list of medications and drug classes mediated by these substrates appears in TABLE 2.)
Evidence suggests omeprazole and its enantiomer esomeprazole have the most potential of the PPIs for drug interactions, as they have been shown to increase blood concentration levels of phenytoin, benzodiazepines, carbamazepine, cilostazol, clarithomycin, and R-warfarin by inhibiting CYP 2C19
. (2,3,29) These interactions do not typically require a dose adjustment.