Effects of Omeprazole and Genetic Polymorphism of CYP2C19 on the Clopidogrel Active Metabolite

Abstract

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 M 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.

Evaluation of Six Proton Pump Inhibitors As Inhibitors of Various Human Cytochromes P450: Focus on Cytochrome P450 2C19

“…The time-dependent shift in IC 50 with (S)-mephenytoin described above is consistent with the observations of Ogilvie et al (2011) and Boulenc et al (2012). In fact, both groups have reported omeprazole (up to 100 M) as a mechanism-based inhibitor of CYP2C19 in HLM and reported K I values ranging from 1.7 to 9.1 M and k inact values ranging from 0.016 to 0.046 min Ϫ1 .…”

“…During the course of the study, it was evident that some of the PPIs behaved as relatively potent inhibitors of CYP2C19 (versus other P450s) and two of them (omeprazole and esomeprazole) also behaved as time-dependent inhibitors. The latter result supports the findings of Ogilvie et al (2011) and Boulenc et al (2012), and the more recent findings of Ohbuchi et al (2012) using 2-oxo-clopidogrel as substrate. Additional studies were conducted with recombinant CYP2C19 (rCYP2C19) using three different substrates , (S)-mephenytoin, and diazepam] and with serum-coincubated human primary hepatocytes using diazepam as substrate.…”

“…Moreover, data for P450s such as CYP2C8, CYP1A2, and CYP2B6 are limited, and there are no reports of various PPIs as time-dependent (metabolism-dependent) inhibitors of P450s (VandenBranden et al, 1996;Ko et al, 1997;Li et al, 2004;Liu et al, 2005;Walsky et al, 2005Walsky et al, , 2006. In fact, there are only two reports describing time-dependent inhibition, with a focus on CYP2C19 (multiple PPIs) or multiple P450s (omeprazole only) (Ogilvie et al, 2011;Boulenc et al, 2012).…”

“…Clopidogrel, a P2Y 12 adenosine diphosphate receptor antagonist, undergoes extensive metabolism to both inactive and active (thiol) metabolites. Although a number of P450s have been shown to catalyze the formation of the active thiol (H4), CYP2C19 has received the most attention; CYP2C19-catalyzed metabolism of clopidogrel is a low K m process in vitro Kazui et al, 2010), and CYP2C19 genotype is associated with antiplatelet activity and circulating levels of H4 (Shuldiner et al, 2009;Furuta et al, 2010;Boulenc et al, 2012). Consequently, the prescribing information for clopidogrel includes a boxed warning regarding the effectiveness of clopidogrel in CYP2C19 poor metabolizers (PMs).…”

Structural Characterization of Human Cytochrome P450 2C19

“…Inter-individual differences in P450 2C19 metabolic capacity can also alter the clearance of omeprazole and structurally related inhibitors of gastric acid secretion leading to differences in clinical outcomes and dosing requirements (6). Omeprazole has also been reported to inactivate P450 2C19, which could contribute to reported drug-drug interactions with clopidogrel (7,8). Efficient metabolism of clopidogrel by P450 2C19 is important for conversion of this pro-drug to an efficacious inhibitor of platelet aggregation (9 -12).…”