Effect of CYP3A5*3 genotype on the pharmacokinetics and antiplatelet effect of clopidogrel in healthy subjects

Kyoung Ah Kim, Pil Whan Park, Ji-Young Park

Research output: Contribution to journalArticle

44 Citations (Scopus)

Abstract

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. Conclusion: The CYP3A5*3 genotype plays a minor role in causing interindividual variability of the disposition of clopidogrel and its antiplatelet effect in humans.

Original languageEnglish
Pages (from-to)589-597
Number of pages9
JournalEuropean Journal of Clinical Pharmacology
Volume64
Issue number6
DOIs
Publication statusPublished - 2008 Jun 1

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clopidogrel
Cytochrome P-450 CYP3A
Healthy Volunteers
Pharmacokinetics
Genotype
Platelet Aggregation
Adenosine Diphosphate

Keywords

  • Clopidogrel
  • CYP3A5*3
  • Cytochrome P450 (CYP3A5)
  • Platelet aggregation
  • SR26334

ASJC Scopus subject areas

  • Pharmacology
  • Pharmacology (medical)

Cite this

Effect of CYP3A5*3 genotype on the pharmacokinetics and antiplatelet effect of clopidogrel in healthy subjects. / Kim, Kyoung Ah; Park, Pil Whan; Park, Ji-Young.

In: European Journal of Clinical Pharmacology, Vol. 64, No. 6, 01.06.2008, p. 589-597.

Research output: Contribution to journalArticle

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N2 - 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. Conclusion: The CYP3A5*3 genotype plays a minor role in causing interindividual variability of the disposition of clopidogrel and its antiplatelet effect in humans.

AB - 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. Conclusion: The CYP3A5*3 genotype plays a minor role in causing interindividual variability of the disposition of clopidogrel and its antiplatelet effect in humans.

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