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.
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.
6,17,18) In 2010, the US Food and Drug Administration (FDA) added a black-box warning for clopidogrel, emphasizing the risk of myocardial infarction (MI), stroke, and cardiovascular death in patients with defective CYP 2C19
In other words, these drugs impair the activity of CYP 2C19
Five distinct human cytochromes mediate amitriptyline N-demethylation in vitro: dominance of CYP 2C19
0 1-2 well (pmol) Krebs-Heinslet Buffer 100 mM None 25 mM Pluronic F68 None None None Substrate CEC Coumarin MFC Concentration 5 mM 3 [micro]M 75 mM Source Ultrafine Sigma- Sigma- Chemicals Aldrich Aldrich Metabolite CHC 7-HC HFC Source Molecular Sigma- Gentest Probes Aldrich Inhibitor positive control Furafylline Tranyl- Sulfa- cypromine phenazole Concentration 100 [micro]M 100 [micro]M 100 [micro]M Source Ultrafine Sigma- Ultrafine Chemicals Aldrich Chemicals Incubation time 30 min 15 min 45 min Excitation wavelength 410 390 410 Emission wavelength 460 460 538 CYP 2C19
2D6 Amount Enzyme/ 0.
Combined inhibitor of CYP 2C19
and 3A4 may raise esomeprazole levels NEXIUM may increase systemic exposure of cilostazol and an active metabolite.
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