Effect of CYP2C9 and SLCO1B1 polymorphisms on the pharmacokinetics and pharmacodynamics of nateglinide in healthy Chinese male volunteers.

Abstract

PURPOSE:

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: Yu Cheng, Guo Wang, Wei Zhang, Lan Fan, Yao Chen, Hong-Hao Zhou
• Journal: European journal of clinical pharmacology (Eur J Clin Pharmacol) Vol. 69 Issue 3 Pg. 407-13 (Mar 2013) ISSN: 1432-1041 [Electronic] Germany
• PMID: 22842957 (Publication Type: Clinical Trial, Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Biomarkers
• Blood Glucose
• Cyclohexanes
• Hypoglycemic Agents
• Liver-Specific Organic Anion Transporter 1
• Organic Anion Transporters
• SLCO1B1 protein, human
• Nateglinide
• Phenylalanine
• CYP2C9 protein, human
• Cytochrome P-450 CYP2C9
• Aryl Hydrocarbon Hydroxylases

Topics

• Administration, Oral
• Area Under Curve
• Aryl Hydrocarbon Hydroxylases (genetics, metabolism)
• Asian People (genetics)
• Biomarkers (blood)
• Blood Glucose (drug effects, metabolism)
• China (epidemiology)
• Cyclohexanes (administration & dosage, blood, pharmacokinetics)
• Cytochrome P-450 CYP2C9
• Genotype
• Half-Life
• Humans
• Hypoglycemic Agents (administration & dosage, blood, pharmacokinetics)
• Liver-Specific Organic Anion Transporter 1
• Male
• Metabolic Clearance Rate
• Nateglinide
• Organic Anion Transporters (genetics, metabolism)
• Pharmacogenetics
• Phenotype
• Phenylalanine (administration & dosage, analogs & derivatives, blood, pharmacokinetics)
• Polymorphism, Single Nucleotide
• Prospective Studies