Influences of different proton pump inhibitors on the anti-platelet function of clopidogrel in relation to CYP2C19 genotypes

Abstract

What is already known about this subject: Active metabolism of clopidogrel is mainly mediated by CYP2C19. There are genetic differences in the activity of CYP2C19. Therefore, active metabolism of clopidogrel is affected by CYP2C19 genotypes. The main metabolizing enzyme of proton pump inhibitors (PPIs) is CYP2C19. Therefore, the anti-platelet function of clopidogrel is attenuated by concomitant use of PPIs. There are differences in the metabolic disposition among different PPIs. Affinity to CYP2C19 differs among different PPIs.

What this study adds: Whether a PPI attenuates the efficacy of clopidogrel depends on CYP2C19. Individuals who are decreased metabolizers, i.e. carriers the allele of CYP2C19*2 and/or *3, are more likely to convert from 'responder' to 'non-responder' to clopidogrel when placed on a concomitant PPI. We found that rabeprazole, whose affinity to CYP2C19 has been considered lower, attenuated the efficacy of clopidogrel. * We tested whether the separate dosing of a PPI and clopidogrel decreased the risk of attenuation of clopidogrel efficacy. We unfortunately found that separate dosing did not avoid the problematic interaction between clopidogrel and a PPI in subject's with CYP2C19*2 and/or CYP2C19*3.

Aims: The efficacy of clopidogrel is influenced by CYP2C19 genotypes and substrates of CYP2C19, such as proton pump inhibitors (PPIs). We assessed the influence of three different PPIs on the anti-platelet function of clopidogrel in relation to CYP2C19 genotype status.

Methods: Thirty-nine healthy volunteers with different CYP2C19 genotypes took clopidogrel 75 mg with or without omeprazole 20 mg, lansoprazole 30 mg or rabeprazole 20 mg in the morning for 7 days. The influence of the three PPIs on the anti-platelet function of clopidogrel was determined. A less than 30% inhibition of platelet aggregation (IPA) during clopidogrel dosing was defined as a 'low responder'. We also examined whether evening dosing of omeprazole could prevent the interaction with clopidogrel dosed in the morning.

Results: In rapid metabolizers (RMs, *1/*1, n=15) of CYP2C19, omeprazole and rabeprazole significantly attenuated the anti-platelet function of clopidogrel. In decreased metabolizers (DMs, carriers of *2 and/or *3, n=24), there was a large variation in IPA and there was a trend but no significant decrease in IPA when placed on a concomitant PPI. Some DMs became 'low-responders' when placed on a concomitant PPI. Evening omeprazole dose in RMs did not seem to cause a significant decrease in IPA in contrast to morning dosing, but did so in DMs.

Conclusions: The three PPIs affected the efficacy of clopidogrel to different degrees. Both omeprazole and rabeprazole significantly decreased IPA in RMs but not DMs, although there was a trend towards lower IPA in DMs. Morning and evening dosing of omeprazole were both associated with lower IPA in DMs.

Figure 1

Schematic demonstration of the study protocol. Firstly, all 39 subjects took 75 mg clopidogrel at 08.00 h for 7 days. Next, all subjects took clopidogrel 75 mg with a different PPI, 20 mg omeprazole, 30 mg lansoprazole or 20 mg rabeprazole. The order of the three PPIs was randomized. All medications were taken once daily at 08.00 h. There was a washout period of at least 2 weeks between the two study periods. In the second study, 30 of 39 subjects took 20 mg omeprazole (OPZ) at 20.00 h and 75 mg clopidogrel at 08.00 h for 7 days. Platelet aggregation induced by 20 µm of ADP was measured before the study and at 4 h after the last dose of clopidogrel on the 7^th day of each study period

Figure 2

Changes in the inhibition of platelet aggregation (IPA) by clopidogrel with different PPIs in the whole group (A) and in different CYP2C19 genotype groups (B). The grey zone indicates the low-responders. The anti-platelet function of clopidogrel was not influenced by any of the three PPIs, omeprazole (OPZ), lansoprazole (LPZ) or rabeprazole (RPZ), in the whole group (A). When separately analyzed according to CYP2C19 genotype groups, statistically significant differences in the inhibition of platelet aggregation by clopidogrel were found (B). This difference was maintained during the concomitant dosing with different PPIs. Omeprazole (OPZ) and rabeprazole (RPZ) significantly attenuated the inhibition of platelet aggregation by clopidogrel in rapid metabolizers (RMs) of CYP2C19 (B). (B): Rapid metabolizer (n = 15) (); Decreased metabolizer (n = 24) ()

Figure 3

Individual changes in inhibition of platelet aggregation by clopidogrel with or without different PPIs. The connecting lines should be used to trace the IPA values for each subject. The order of three PPIs was randomized. In the rapid metabolizers of CYP2C19 (RM), omeprazole (OPZ) and lansoprazole (LPZ) influenced the efficacy of clopidogrel, but did not decrease it to the level of low-responders except in one case. In the decreased metabolizers (DM), there was a wide distribution in the degree of inhibition of platelet aggregation by clopidogrel. Of 24 decreased metabolizers, 16 were not in the low-responder group. PPIs affected the efficacy of clopidogrel. Of the 16 subjects not in the low-responder group, five, one and two became non-responders after concomitant dosing with omeprazole, lansoprazole or rabeprazole (RPZ), respectively. Dotted lines indicate the IPA of poor metabolizers (*2/*3)

Figure 4

The effect of morning (Mor) or evening (Eve) dose of omeprazole on the efficacy of clopidogrel in the whole group (A) and in different CYP2C19 genotype groups (B). Decreased efficacy of clopidogrel by the concomitant dosing of omeprazole was not restored by the separate dosing of omeprazole as a whole (A). When separately analyzed according to CYP2C19 genotype, the decreased efficacy of clopidogrel with concomitant dosing with omeprazole was restored by a separate dosing of omeprazole in the rapid metabolizers (RMs) of CYP2C19. In the decreased metabolizers (DM), omeprazole appeared to decrease the efficacy of clopidogrel, which seemed not to be restored by the separate dosing of omeprazole. (B): Rapid metabolizer (n = 14) (); Decreased metabolizer (n = 16) ()

Figure 5

Individual changes in inhibition of platelet aggregation by clopidogrel with morning (Mor) or evening (Eve) dosing of omeprazole in different CYP2C19 genotype groups. The connecting lines should be used to trace the IPA of each subject. The order of three PPIs was randomized. In the rapid metabolizers of CYP2C19 (RM), none became a low-responder (A). In the decreased metabolizers (DMs), four of seven subjects classified as low-responders during concomitant dosing of clopidogrel and omeprazole become responders, but two subjects not classed as low-responders during concomitant dosing with clopidogrel and omeprazole became low-responders after the separate dosing of clopidogrel and a PPI. The dotted line indicates the IPA of a poor metabolizer (*2/*3)