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


CONCLUSIONS
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.


OBJECTIVE
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.
Furuta
Takahisa
T
Center for Clinical Research, Department of Pharmacology, Hamamatsu University School of Medicine, Hamamatsu 431-3192, Japan. furuta@hama-med.ac.jp
Iwaki
Takayuki
T
Umemura
Kazuo
K
D001189:Aryl Hydrocarbon Hydroxylases / Q000235:genetics*; D001792:Blood Platelets / Q000187:drug effects*; D000077144:Clopidogrel; D065731:Cytochrome P-450 CYP2C19; D004347:Drug Interactions / Q000235:genetics; D004359:Drug Therapy, Combination; D005260:Female; D005838:Genotype; D006801:Humans; D008297:Male; D010974:Platelet Aggregation / Q000187:drug effects / Q000235:genetics; D010975:Platelet Aggregation Inhibitors / Q000494:pharmacology*; D054328:Proton Pump Inhibitors / Q000494:pharmacology*; D013223:Statistics as Topic; D013988:Ticlopidine / Q000031:analogs & derivatives* / Q000494:pharmacology; D055815:Young Adult
D010975:Platelet Aggregation Inhibitors; D054328:Proton Pump Inhibitors; D000077144:Clopidogrel; D001189:Aryl Hydrocarbon Hydroxylases; C045793:CYP2C19 protein, human; D065731:Cytochrome P-450 CYP2C19; D013988:Ticlopidine