Polymorphism in CYP2C8 is associated with reduced plasma concentrations of repaglinide

Clin Pharmacol Ther. 2003 Oct;74(4):380-7. doi: 10.1016/S0009-9236(03)00228-5.


Objective: Our objective was to investigate the effects of genetic polymorphisms of cytochrome P450 (CYP) 2C8 on the pharmacokinetics and pharmacodynamics of the meglitinide analog antidiabetic drug repaglinide.

Methods: We genotyped 28 healthy volunteers who had participated in our pharmacokinetic studies on repaglinide for variant alleles of the CYP2C8 gene. Each subject ingested a 0.25-mg dose of repaglinide, and plasma drug and blood glucose concentrations were monitored for 7 hours after dosing.

Results: There were 19 subjects (68%) with the CYP2C8*1/*1 genotype (wild type), 6 subjects (21%) with the CYP2C8*1/*3 genotype, and 3 subjects (11%) with the CYP2C8*1/*4 genotype. In the 3 genotypic groups, the mean +/- SD area under the plasma repaglinide concentration-time curve from time 0 to infinity [AUC(0- infinity )] was 5.8 +/- 2.5 ng. h/mL for CYP2C8*1/*1, 3.6 +/- 0.9 ng. h/mL for CYP2C8*1/*3, and 5.1 +/- 3.6 ng. h/mL for CYP2C8*1/*4. The mean AUC(0- infinity ) of repaglinide was 45% (P <.005) lower and the peak concentration in plasma was 39% lower (P <.05) in subjects with the CYP2C8*1/*3 genotype compared with those with the CYP2C8*1/*1 genotype. No statistically significant differences were found in the blood glucose response to repaglinide between the genotypes.

Conclusions: Unexpectedly, the CYP2C8*3 variant allele was associated with reduced plasma concentrations of repaglinide. The effects of CYP2C8 polymorphisms on the pharmacokinetics of CYP2C8 substrates warrant further study.

Publication types

  • Clinical Trial
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Alleles
  • Area Under Curve
  • Aryl Hydrocarbon Hydroxylases / genetics*
  • Blood Glucose / drug effects
  • Carbamates / blood
  • Carbamates / pharmacokinetics*
  • Carbamates / pharmacology
  • Cytochrome P-450 CYP2C8
  • Female
  • Genotype
  • Half-Life
  • Humans
  • Hypoglycemic Agents / blood
  • Hypoglycemic Agents / pharmacokinetics*
  • Hypoglycemic Agents / pharmacology
  • Linear Models
  • Male
  • Piperidines / blood
  • Piperidines / pharmacokinetics*
  • Piperidines / pharmacology
  • Polymorphism, Genetic*


  • Blood Glucose
  • Carbamates
  • Hypoglycemic Agents
  • Piperidines
  • repaglinide
  • Aryl Hydrocarbon Hydroxylases
  • CYP2C8 protein, human
  • Cytochrome P-450 CYP2C8