Effect of CYP3A5*3 genotype on the pharmacokinetics and antiplatelet effect of clopidogrel in healthy subjects.
OBJECTIVE
Clopidogrel is activated by cytochrome P450 3A (CYP3A) to generate an active metabolite that inhibits adenosine diphosphate (ADP)-induced platelet aggregation through irreversible binding to the platelet P2Y12 receptor. The objective of this study was to assess the effect of the CYP3A5 genotype on the pharmacokinetics and antiplatelet effect of clopidogrel in healthy subjects.


METHODS
Twenty-two healthy subjects (CYP3A5*1/*1, n = 6; CYP3A5*1/*3, n = 8; CYP3A5*3/*3, n = 8) were recruited. After the administration of a loading dose of 300 mg of clopidogrel followed by 75 mg once daily for 6 days, plasma concentrations of clopidogrel and SR26334, an inactive metabolite, were measured for 24 h. The antiplatelet effect of clopidogrel was also measured, by determining the inhibition of ADP-induced platelet aggregation for 168 h, according to CYP3A5 genotype.


RESULTS
Mean plasma concentration profiles of clopidogrel and SR26334 were comparable between CYP3A5 genotype groups. In addition, the CYP3A5 genotype did not affect the pharmacokinetics of either clopidogrel or SR26334. CYP3A5 genotype also did not modulate the inhibitory effect of clopidogrel on platelet aggregation.


CONCLUSIONS
The CYP3A5*3 genotype plays a minor role in causing interindividual variability of the disposition of clopidogrel and its antiplatelet effect in humans.
Kim
Kyoung-Ah
KA
Department of Clinical Pharmacology & Toxicology, Anam Hospital, Korea University College of Medicine, 126-1, Anam-dong 5-ga, Sungbuk-gu, Seoul 136-705, South Korea.
Park
Pil-Whan
PW
Park
Ji-Young
JY
D000328:Adult; D000077144:Clopidogrel; D051544:Cytochrome P-450 CYP3A / Q000235:genetics*; D005838:Genotype; D006801:Humans; D010975:Platelet Aggregation Inhibitors / Q000493:pharmacokinetics / Q000494:pharmacology*; D013988:Ticlopidine / Q000031:analogs & derivatives* / Q000493:pharmacokinetics / Q000494:pharmacology
D010975:Platelet Aggregation Inhibitors; D000077144:Clopidogrel; C510164:CYP3A5 protein, human; D051544:Cytochrome P-450 CYP3A; C510163:CYP3A4 protein, human; D013988:Ticlopidine