title: Effects of omeprazole and genetic polymorphism of CYP2C19 on the clopidogrel active metabolite.
abstract: Clopidogrel is an antiplatelet agent widely used in cardiovascular diseases and an inactive prodrug that needs to be converted to an active metabolite in two sequential metabolic steps. Several CYP450 isoforms involved in these two steps have been described, although the relative contribution in vivo of each enzyme is still under debate. CYP2C19 is considered to be the major contributor to active metabolite formation. In the current study, net CYP2C19 contribution to the active metabolite formation was determined from exposure of the active metabolite in two clinical studies (one phase I study with well balanced genetic polymorphic populations and a meta-analysis with a total of 396 healthy volunteers) at different clopidogrel doses. CYP2C19 involvements were estimated to be from 58 to 67% in intermediate metabolizers (IMs), from 58 to 72% in extensive metabolizers (EMs), and from 56 to 74% in ultrarapid metabolizers (UMs), depending on the study and the dose. For this purpose, a static model was proposed to estimate the net contribution of a given enzyme to the secondary metabolite formation. This static model was compared with a dynamic approach (Simcyp model) and showed good consistency. In parallel, in vitro investigations showed that omeprazole is a mechanism-based inhibitor of CYP2C19 with K(I) of 8.56 μM and K(inact) of 0.156 min(-1). These values were combined with the net CYP2C19 contribution to the active metabolite formation, through a static approach, to predict the inhibitory effect at 80-mg omeprazole doses in EM, IM, and UM CYP2C19 populations, with good consistency, compared with observed clinical values.
authors: Drug Disposition Domain, Disposition Safety and Animal Research, sanofi-aventis, 371 rue du Professeur J. Blayac, 34184 Montpellier cedex 04, France. xavier.boulenc@sanofi-aventis.com
authors: Xavier
authors: X
authors: Boulenc
authors: Nassim
authors: N
authors: Djebli
authors: Juan
authors: J
authors: Shi
authors: Laurent
authors: L
authors: Perrin
authors: William
authors: W
authors: Brian
authors: Robert
authors: R
authors: Van Horn
authors: Fabrice
authors: F
authors: Hurbin
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D001189:Aryl Hydrocarbon Hydroxylases / Q000235:genetics* / Q000502:physiology; D000077144:Clopidogrel; D018592:Cross-Over Studies; D065731:Cytochrome P-450 CYP2C19; D005260:Female; D006801:Humans; D008297:Male; D008862:Microsomes, Liver / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism; D008875:Middle Aged; D009853:Omeprazole / Q000494:pharmacology*; D011110:Polymorphism, Genetic / Q000502:physiology*; D013988:Ticlopidine / Q000031:analogs & derivatives* / Q000378:metabolism
chemical_list: D000077144:Clopidogrel; D001189:Aryl Hydrocarbon Hydroxylases; C045793:CYP2C19 protein, human; D065731:Cytochrome P-450 CYP2C19; D009853:Omeprazole; D013988:Ticlopidine