title: Effects of functional CYP2C8,CYP2C9,CYP3A5,and ABCB1 genetic variants on the pharmacokinetics of insulin sensitizer pioglitazone in Chinese Han individuals.
abstract: Pioglitazone is a thiazolidinedione antihyperglycemic drug with insulin-sensitizing properties. We investigated whether the variant genotypes of cytochrome P450 2C8 (CYP2C8), CYP2C9, CYP3A5 and transporter ABCB1 influence the pharmacokinetic phenotype of the substrate pioglitazone in Chinese individuals.
  
  
  
  Single-nucleotide polymorphisms were determined by the PCR-restriction fragment length polymorphism method in 244 (CYP2C8 and CYP2C9) healthy Chinese Han individuals. After a single oral dose of 30 mg pioglitazone, the plasma concentrations of the parent drug and of two major active metabolites M-III and M-IV were measured using a validated LC-MS/MS in 21 (genotyping CYP3A5 and ABCB1) of these 244 volunteers.
  
  
  
  The results confirmed that the unique frequencies of CYP2C8*2 (0.0%), CYP2C8*3 (0.0%), and CYP2C9*2 (0.0%) alleles were significantly different from those reported in Whites and Africans, and there were only 10 variant CYP2C9*1/*3 heterozygous (CYP2C9*3 carriers) among 244 Chinese individuals. These results were similar to those reported in Asian ethnic populations, including the Chinese. Unexpectedly, the pioglitazone AUC0-48 in CYP2C9*3 carriers was lower (50.8%), whereas the AUC0-48 ratios of metabolites M-III/pioglitazone and M-IV/pioglitazone increased to 134.3 and 155.8%, respectively, compared with the wild-type CYP2C9*1/*1 homozygous. Moreover, this phenomenon was not observed in individuals with genetic variants of CYP3A5*3 and ABCB1 (C1236T).
  
  
  
  The present research suggests that the CYP2C8, CYP3A5, and ABCB1 genes play no significant role in the interindividual variation of pioglitazone pharmacokinetics, whereas CYP2C9*3 carriers are likely to accelerate the metabolism of this antidiabetic drug in the Chinese Han ethnic population.
authors.affiliation: aDepartment of Pharmacology,School of Basic Medical Sciences, Peking University bDepartment of Pharmacokinetics, Institute of Clinical Pharmacology, Peking University First Hospital, Beijing, China cDepartment of Drug Metabolism & Pharmacokinetics, Biogen, Cambridge, Massachusetts, USA.
authors.forename: Sheng-Ju
authors.initials: SJ
authors.lastname: Yin
authors.forename: Hui-Min
authors.initials: HM
authors.lastname: Qi
authors.forename: Xin
authors.initials: X
authors.lastname: Wang
authors.forename: Pu
authors.initials: P
authors.lastname: Zhang
authors.forename: Yuan
authors.initials: Y
authors.lastname: Lu
authors.forename: Min-Ji
authors.initials: MJ
authors.lastname: Wei
authors.forename: Pu
authors.initials: P
authors.lastname: Li
authors.forename: Guang-Zhao
authors.initials: GZ
authors.lastname: Qi
authors.forename: Ya-Qing
authors.initials: YQ
authors.lastname: Lou
authors.forename: Chuang
authors.initials: C
authors.lastname: Lu
authors.forename: Guo-Liang
authors.initials: GL
authors.lastname: Zhang
mesh_terms: D018435:ATP Binding Cassette Transporter, Subfamily B / Q000235:genetics; D000284:Administration, Oral; D000328:Adult; D044466:Asian People / Q000208:ethnology / Q000235:genetics*; D002681:China / Q000208:ethnology; D065727:Cytochrome P-450 CYP2C8 / Q000235:genetics; D065729:Cytochrome P-450 CYP2C9 / Q000235:genetics; D051544:Cytochrome P-450 CYP3A / Q000235:genetics; D005260:Female; D053263:Gene Regulatory Networks; D005838:Genotype; D006801:Humans; D007004:Hypoglycemic Agents / Q000008:administration & dosage* / Q000493:pharmacokinetics; D008297:Male; D000071184:Pharmacogenomic Variants; D000077205:Pioglitazone; D020641:Polymorphism, Single Nucleotide; D045162:Thiazolidinediones / Q000008:administration & dosage* / Q000493:pharmacokinetics; D055815:Young Adult
chemical_list: C513055:ABCB1 protein, human; D018435:ATP Binding Cassette Transporter, Subfamily B; D007004:Hypoglycemic Agents; D045162:Thiazolidinediones; C450260:CYP2C9 protein, human; D065729:Cytochrome P-450 CYP2C9; C450259:CYP2C8 protein, human; C510164:CYP3A5 protein, human; D065727:Cytochrome P-450 CYP2C8; D051544:Cytochrome P-450 CYP3A; D000077205:Pioglitazone