Journal of Korean Society for Clinical Pharmacology and Therapeutics (임상약리학회지)

Korean Society for Clinical Pharmacology and Therapeutics (대한임상약리학회)
권호 표지

Pharmacokinetics of Rosiglitazone According to CYP2C8 Genotype in Korean Population

한국인에서 CYP2C8 유전형에 따른 Rosiglitazone 약동학 연구

  • Cho, Joo-Youn (Department of Pharmacology and Clinical Pharmacology Unit, College of Medicine, Seoul National University and Hospital) ;
  • Lim, Hyeong-Seok (National Cancer Center) ;
  • Suh, You-Sin (Metagentech Co.) ;
  • Chung, Jae-Yong (Department of Pharmacology and Clinical Pharmacology Unit, College of Medicine, Seoul National University and Hospital) ;
  • Hong, Kyoung-Sup (Department of Pharmacology and Clinical Pharmacology Unit, College of Medicine, Seoul National University and Hospital) ;
  • Yi, So-Young (Department of Pharmacology and Clinical Pharmacology Unit, College of Medicine, Seoul National University and Hospital) ;
  • Yu, Kyung-Sang (Department of Pharmacology and Clinical Pharmacology Unit, College of Medicine, Seoul National University and Hospital) ;
  • Jang, In-Jin (Department of Pharmacology and Clinical Pharmacology Unit, College of Medicine, Seoul National University and Hospital) ;
  • Shin, Sang-Goo (Department of Pharmacology and Clinical Pharmacology Unit, College of Medicine, Seoul National University and Hospital)
  • 조주연 (서울대학교 의과대학 약리학교실,서울대학교병원 임상약리실) ;
  • 임형석 (국립암센터) ;
  • 서유신 (메타젠텍) ;
  • 정재용 (서울대학교 의과대학 약리학교실,서울대학교병원 임상약리실) ;
  • 홍경섭 (서울대학교 의과대학 약리학교실,서울대학교병원 임상약리실) ;
  • 이소영 (서울대학교 의과대학 약리학교실,서울대학교병원 임상약리실) ;
  • 유경상 (서울대학교 의과대학 약리학교실,서울대학교병원 임상약리실) ;
  • 장인진 (서울대학교 의과대학 약리학교실,서울대학교병원 임상약리실) ;
  • 신상구 (서울대학교 의과대학 약리학교실,서울대학교병원 임상약리실)
  • Published : 2005.12.30

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Abstract

Background : Cytochrome P450 (CYP) 2C8 is the major enzyme that metabolizes many xenobiotics, including the anti-cancer drug paclitaxel and anti-diabetic drug rosiglitazone. Genetic polymorphisms of the human CYP2C8 gene were identified in Korean population, and their effects on the phenotype were evaluated on the basis of the in vivo pharmacokinetics of rosiglitazone. Methods : We surveyed genetic variations in all exons, exon-intron junctions, and promoter region of human CYP2C8 gene from 306 unrelated healthy Koreans by using fluorescence two-dimensional gene scanning (TDGS) and sequence analyses. Pharmacokinetic parameters of rosiglitazone after 8 mg single dose in relation to the corresponding polymorphisms were estimated. Results : Genetic analysis revealed the existence of eleven single nucleotide polymorphisms (SNPs). Two synonymous SNPs, three non-synonymous SNPs and one nucleotide deletion were identified in the coding region, two SNPs in intron, and three SNPs in promoter region. Allele frequencies of 324A>G, 37OC>T (Rl24W) in exon2, 475delA (CYP2C8*5) in exon3, 917T>C (L306P) in exon6, 1171C>A (L391M), and 123OC>T in exon8 were 0.005, 0.002, 0.002, 0.002, 0.002, and 0.26, respectively. Three common SNPs, -411T>C, -370T>G, and -271C>A in the 5'-flanking region were frequent at 0.382, 0.330, and 0.116, respectively. The functional significance of the two upstream polymorphisms (CYP2C8*1C and * lD) and R124W and 475delA alleles was investigated in pharmacokinetics of rosiglitazone. Pharmacokinetic characteristics of rosiglitazone were not different in single heterozygous subject for either 370C>T or 475delA and in homozygous subjects for CYP2C8*lC and CYP2C8*lD, compared with homozygous wild type subjects. Conclusion : Although several genetic polymorphisms for CYP2C8 were identified in Koreans, there was no evidence that either upstream and non-synonymous SNPs gave rise to altered pharmacokinetics of rosiglitazone.

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