Pharmacokinetics of rosiglitazone according to CYP2C8 genotype in Korean population

Joo Youn Cho, Hyeong Seok Lim, Yousin Suh, Jae Yong Chung, Kyoung Sup Hong, So Young Yi, Kyung Sang Yu, In Jin Jang, Sang Goo Shin

Research output: Contribution to journalArticle

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, 370C>T (R124W) in exon2, 475delA (CYP2C8*5) in exon3, 917T>C (L306P) in exon6, 1171C>A (L391M), and 1230C>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 *1D) 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*1C and CYP2C8*1D, 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.

Original languageEnglish (US)
Pages (from-to)142-156
Number of pages15
JournalJournal of Korean Society for Clinical Pharmacology and Therapeutics
Volume13
Issue number2
StatePublished - 2005
Externally publishedYes

Fingerprint

rosiglitazone
Single Nucleotide Polymorphism
Pharmacokinetics
Genotype
Population
Genetic Polymorphisms
Genetic Promoter Regions
Introns
Exons
Genes
5' Flanking Region
Xenobiotics
Paclitaxel
Cytochrome P-450 CYP2C8
Gene Frequency
Pharmaceutical Preparations
Cytochrome P-450 Enzyme System
Sequence Analysis

Keywords

  • CYP2C8
  • Haplotype
  • Pharmacokinetics
  • Polymorphism
  • Rosiglitazone
  • TDGS

ASJC Scopus subject areas

  • Pharmacology (medical)

Cite this

Pharmacokinetics of rosiglitazone according to CYP2C8 genotype in Korean population. / Cho, Joo Youn; Lim, Hyeong Seok; Suh, Yousin; Chung, Jae Yong; Hong, Kyoung Sup; Yi, So Young; Yu, Kyung Sang; Jang, In Jin; Shin, Sang Goo.

In: Journal of Korean Society for Clinical Pharmacology and Therapeutics, Vol. 13, No. 2, 2005, p. 142-156.

Research output: Contribution to journalArticle

Cho, JY, Lim, HS, Suh, Y, Chung, JY, Hong, KS, Yi, SY, Yu, KS, Jang, IJ & Shin, SG 2005, 'Pharmacokinetics of rosiglitazone according to CYP2C8 genotype in Korean population', Journal of Korean Society for Clinical Pharmacology and Therapeutics, vol. 13, no. 2, pp. 142-156.
Cho, Joo Youn ; Lim, Hyeong Seok ; Suh, Yousin ; Chung, Jae Yong ; Hong, Kyoung Sup ; Yi, So Young ; Yu, Kyung Sang ; Jang, In Jin ; Shin, Sang Goo. / Pharmacokinetics of rosiglitazone according to CYP2C8 genotype in Korean population. In: Journal of Korean Society for Clinical Pharmacology and Therapeutics. 2005 ; Vol. 13, No. 2. pp. 142-156.
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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, 370C>T (R124W) in exon2, 475delA (CYP2C8*5) in exon3, 917T>C (L306P) in exon6, 1171C>A (L391M), and 1230C>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 *1D) 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*1C and CYP2C8*1D, 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.",
keywords = "CYP2C8, Haplotype, Pharmacokinetics, Polymorphism, Rosiglitazone, TDGS",
author = "Cho, {Joo Youn} and Lim, {Hyeong Seok} and Yousin Suh and Chung, {Jae Yong} and Hong, {Kyoung Sup} and Yi, {So Young} and Yu, {Kyung Sang} and Jang, {In Jin} and Shin, {Sang Goo}",
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T1 - Pharmacokinetics of rosiglitazone according to CYP2C8 genotype in Korean population

AU - Cho, Joo Youn

AU - Lim, Hyeong Seok

AU - Suh, Yousin

AU - Chung, Jae Yong

AU - Hong, Kyoung Sup

AU - Yi, So Young

AU - Yu, Kyung Sang

AU - Jang, In Jin

AU - Shin, Sang Goo

PY - 2005

Y1 - 2005

N2 - 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, 370C>T (R124W) in exon2, 475delA (CYP2C8*5) in exon3, 917T>C (L306P) in exon6, 1171C>A (L391M), and 1230C>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 *1D) 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*1C and CYP2C8*1D, 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.

AB - 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, 370C>T (R124W) in exon2, 475delA (CYP2C8*5) in exon3, 917T>C (L306P) in exon6, 1171C>A (L391M), and 1230C>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 *1D) 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*1C and CYP2C8*1D, 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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