The effect of CYP2C19 genotype on the time course of platelet aggregation inhibition after clopidogrel administration.
We evaluated the effect of CYP2C19 genotype over time on the antiplatelet response of clopidogrel in healthy subjects. Seventy subjects enrolled for a pharmacodynamic study and 22 subjects for a pharmacokinetic and pharmacodynamic study took 300 mg clopidogrel on the first day and 75 mg once daily for six consecutive days. The subjects with CYP2C19 poor metabolizers (PM, N = 22) and intermediate metabolizers (IM, N = 37) had significantly delayed time to inhibition of platelet aggregation (IPA) compared with CYP2C19 extensive metabolizers (EM, N = 33) (12 vs. 9 vs. 2 hours as median Tmax , P < .05) after a 300 mg of clopidogrel. During maintenance doses of clopidogrel, IPA values of only CYP2C19 PM subjects were gradually decreased from 30.0 ± 21.9% on day 2 to 23.7 ± 16.6% on day 8 (P > .05 for time effect; P < .05 for time and genotype interaction effect). CYP2C19 PM had decreased Cmax and AUC of thiol metabolite compared with CYP2C19 EM (0.42- and 0.37-fold on day 1, P < .01; 0.39- and 0.34-fold on day 7, P < .01, respectively). Delayed time to reach maximal IPA as well as decreased IPA may influence the increased risk of the acute cardiac events in CYP2C19 PM and IM.
Department of Pharmacology and PharmacoGenomics Research Center, Inje University College of Medicine, Busan, Republic of Korea; Department of Clinical Pharmacology, Inje University Busan Paik Hospital, Busan, Republic of Korea.
Ho-Sook
HS
Kim
Doo-Yeoun
DY
Cho
Bo-Min
BM
Park
Soo-Kyoung
SK
Bae
Yune-Jung
YJ
Yoon
Minkyung
M
Oh
Jong-Lyul
JL
Ghim
Eun-Young
EY
Kim
Dong-Hyun
DH
Kim
Jae-Gook
JG
Shin
D000328:Adult; D019540:Area Under Curve; D044466:Asian People / Q000235:genetics; D000077144:Clopidogrel; D065731:Cytochrome P-450 CYP2C19 / Q000235:genetics* / Q000378:metabolism; D005838:Genotype; D006801:Humans; D008297:Male; D010974:Platelet Aggregation / Q000187:drug effects*; D010975:Platelet Aggregation Inhibitors / Q000097:blood / Q000493:pharmacokinetics / Q000494:pharmacology*; D020641:Polymorphism, Single Nucleotide; D013438:Sulfhydryl Compounds / Q000097:blood; D013988:Ticlopidine / Q000031:analogs & derivatives* / Q000097:blood / Q000493:pharmacokinetics / Q000494:pharmacology; D055815:Young Adult
D010975:Platelet Aggregation Inhibitors; D013438:Sulfhydryl Compounds; D000077144:Clopidogrel; D065731:Cytochrome P-450 CYP2C19; D013988:Ticlopidine
CYP2C19 genotype; clopidogrel; time course of platelet aggregation inhibition