한국인 건강 피험자에서 Cytochrome P450 2C19 유전적다형성과 Ketoconazole 병용투여가 Clopidogrel 투여 후 혈소판응집 반응에 미치는 영향

Effect of Cytochrome P450 2C19 Genetic Polymorphism and Coadministration with Ketoconazole on the Platelet Aggregation Response to Clopidogrel in Korean Healthy Subjects

  • 김정렬 (서울대학교 의과대학 약리학교실) ;
  • 김선정 (서울대학교 의과대학 약리학교실) ;
  • 김화숙 (서울대학교 의과대학 약리학교실) ;
  • 엄소영 (서울대학교 의과대학 약리학교실) ;
  • 신광희 (서울대학교 의과대학 약리학교실) ;
  • 조주연 (서울대학교 의과대학 약리학교실) ;
  • 유경상 (서울대학교병원 임상약리학과) ;
  • 신상구 (서울대학교 의과대학 약리학교실) ;
  • 장인진 (서울대학교 의과대학 약리학교실)
  • Kim, Jung-Ryul (Department of Pharmacology, Seoul National University College of Medicine) ;
  • Kim, Seon-Jeong (Department of Pharmacology, Seoul National University College of Medicine) ;
  • Kim, Hwa-Sook (Department of Pharmacology, Seoul National University College of Medicine) ;
  • Eum, So-Young (Department of Pharmacology, Seoul National University College of Medicine) ;
  • Shin, Kwang-Hee (Department of Pharmacology, Seoul National University College of Medicine) ;
  • Cho, Joo-Youn (Department of Pharmacology, Seoul National University College of Medicine) ;
  • Yu, Kyung-Sang (Department of Clinical Pharmacology, Seoul National University Hospital) ;
  • Shin, Sang-Goo (Department of Pharmacology, Seoul National University College of Medicine) ;
  • Jang, In-Jin (Department of Pharmacology, Seoul National University College of Medicine)
  • 투고 : 2009.04.24
  • 심사 : 2009.05.31
  • 발행 : 2009.06.30

초록

Background: Clopidogrel is a prodrug converted to active metabolite mainly by cytochrome P450 (CYP) enzyme, and provides clinical benefitwith wide interindividual variability. We investigated to evaluate the effect of CYP2C19 genetic polymorphism and coadministration with ketoconazole on the platelet aggregation response to clopidogrel. Methods: An open-label, two-treatment, two-period, one-way crossover study with a drug-free period of five days or more was conducted in healthy male volunteers. First, a single dose of 300 mg clopidogrel was administered to carriers of at least one CYP2C19 loss-of-function allele (n=10) and non-carriers (n = 12). After a drug-free period, a single dose of 300 mg clopidogrel was administered with400 mg ketoconazole daily for 3 days. Platelet aggregation was measured at baseline, 4 h, 6 h, and 24 h using Chronolog Lumi-Aggregometer. Results: Maximal platelet aggregation at baseline was not different across CYP2C19 genotype. CYP2C19 loss-of-function allele carriers had significantlyless reduction in platelet aggregation at 24 h than non-carriers whether clopidogrel was administered alone (P=0.018) or with ketoconazole (P=0.011). In addition, relative inhibition of platelet aggregation at 24 h was lower after coadministration with ketoconazole than clopidogrel alone (P<0.001). Conclusions: Platelet aggregation response to clopidogrel was affected by CYP2C19 genetic polymorphism and coadministration with ketoconazole.

키워드

참고문헌

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