title: Effect of CYP2C9 and SLCO1B1 polymorphisms on the pharmacokinetics and pharmacodynamics of nateglinide in healthy Chinese male volunteers.
abstract: OBJECTIVE
  Nateglinide is commonly used in the treatment of patients with type 2 diabetes mellitus. Our objective was to assess the association between CYP2C9 and SLCO1B1 polymorphisms and the metabolism of nateglinide in healthy Chinese male volunteers.
  
  
  METHODS
  A total of 35 healthy Chinese male volunteers with different CYP2C9 and SLCO1B1 genotypes were given a single oral dose of 120 mg nateglinide. Plasma concentrations of nateglinide and blood glucose level were measured up to 8 h.
  
  
  RESULTS
  In subjects with the CYP2C9*1/*3 & 521TT, CYP2C9*1/*1 & 521TC/CC and CYP2C9*1/*3 & 521TC genotype, AUC(0-∞) of nateglinide was 56 %, 34 % and 56 % higher (P = 0.002, P = 0.041 and P = 0.013, respectively), and the CL/F of nateglinide was 35 %, 11 % and 36 % lower (P = 0.000, P = 0.003 and P = 0.002, respectively) than that in the reference group. When only considering 521 T>C polymorphism, it had no significant association with the pharmacokinetics of nateglinide. CYP2C9*3 and 521 T>C polymorphisms were the significant predictors of the AUC(0-∞) and CL/F of nateglinide (adjusted multiple R(2) = 34 % and 43 %, respectively) according to multiple linear regression analyses, but they have no significant association with changes in the blood glucose-lowering effect of nateglinide.
  
  
  CONCLUSIONS
  Both SLCO1B1 521 T>C and the CYP2C9*3 polymorphisms can significantly affect the pharmacokinetics of nateglinide, but they could only partially explain the interindividual variability of plasma concentration of nateglinide. Moreover, 521 T>C and the CYP2C9*3 polymorphisms have no effect on pharmacodynamics of nateglinide in healthy Chinese male subjects.
authors: Pharmacogenetics Research Institute, Institute of Clinical Pharmacology, Central South University, Changsha, Hunan 410078, China.
authors: Yu
authors: Y
authors: Cheng
authors: Guo
authors: G
authors: Wang
authors: Wei
authors: W
authors: Zhang
authors: Lan
authors: L
authors: Fan
authors: Yao
authors: Y
authors: Chen
authors: Hong-Hao
authors: HH
authors: Zhou
mesh_terms: D000284:Administration, Oral; D019540:Area Under Curve; D001189:Aryl Hydrocarbon Hydroxylases / Q000235:genetics* / Q000378:metabolism; D044466:Asian People / Q000235:genetics*; D015415:Biomarkers / Q000097:blood; D001786:Blood Glucose / Q000187:drug effects* / Q000378:metabolism; D002681:China / Q000453:epidemiology; D003510:Cyclohexanes / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics*; D065729:Cytochrome P-450 CYP2C9; D005838:Genotype; D006207:Half-Life; D006801:Humans; D007004:Hypoglycemic Agents / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics*; D027381:Liver-Specific Organic Anion Transporter 1; D008297:Male; D008657:Metabolic Clearance Rate; D000077715:Nateglinide; D027361:Organic Anion Transporters / Q000235:genetics* / Q000378:metabolism; D010597:Pharmacogenetics; D010641:Phenotype; D010649:Phenylalanine / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000097:blood / Q000493:pharmacokinetics; D020641:Polymorphism, Single Nucleotide; D011446:Prospective Studies
chemical_list: D015415:Biomarkers; D001786:Blood Glucose; D003510:Cyclohexanes; D007004:Hypoglycemic Agents; D027381:Liver-Specific Organic Anion Transporter 1; D027361:Organic Anion Transporters; C503999:SLCO1B1 protein, human; D000077715:Nateglinide; D010649:Phenylalanine; C450260:CYP2C9 protein, human; D065729:Cytochrome P-450 CYP2C9; D001189:Aryl Hydrocarbon Hydroxylases