The impact of CYP2C8 polymorphism and grapefruit juice on the pharmacokinetics of repaglinide

Br J Clin Pharmacol. 2006 Jan;61(1):49-57. doi: 10.1111/j.1365-2125.2005.02516.x.


Aims: The primary aim of the study was to investigate the possible effect of the CYP2C8*3 allele and of grapefruit juice on the pharmacokinetics of repaglinide. Furthermore, the impact of a single dose of grapefruit juice on the pharmacokinetics of repaglinide in relation to dose.

Methods: Thirty-six healthy male subjects, genotyped for CYP2C8*3 (11 genotyped as CYP2C8*1/*3, one as CYP2C8*3/*3 and 24 as CYP2C8*1/*1), participated in a randomized, cross-over trial. In the two phases, the subjects drank 300 mL water or 300 mL grapefruit juice, in randomized order, 2 h before administration of a single dose of either 0.25 mg or 2 mg repaglinide.

Results: Neither the mean AUC(0-infinity) (geometric mean ratio: 1.01; 95% CI: 0.93-1.1, P = 0.88) nor the mean C(max) (geometric mean ratio: 1.05; 95% CI: 0.94-1.2, P = 0.35) of repaglinide were statistically significantly different in the group carrying the CYP2C8*3 mutant allele compared with wild-types. Grapefruit juice caused a 19% decrease in the geometric mean ratio of the 3-hydroxyquinidine to quinidine ratio (difference: 0.81; 95% CI: 0.75-0.87, P < 0.0001), which was used as an index of CYP3A4 activity, and an increase in the mean AUC(0-infinity) of repaglinide (geometric mean ratio: 1.13; 95% CI: 1.04-1.2, P = 0.0048), but had no statistically significant effect on the t(1/2). There was no statistically significant difference in blood glucose concentration in subjects who had or had not ingested grapefruit juice. The effect was more pronounced at the low dose of repaglinide (0.25 mg) than at the therapeutic dose of 2 mg.

Conclusions: The pharmacokinetics of repaglinide in subjects carrying the CYP2C8*3 mutant allele did not differ significantly from those in the wild-types. Grapefruit juice increased the bioavailability of repaglinide, suggesting significant intestinal elimination of the drug which was assumed to be primarily mediated by CYP3A4 in the gut.

Publication types

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

MeSH terms

  • Administration, Oral
  • Adult
  • Area Under Curve
  • Aryl Hydrocarbon Hydroxylases / genetics*
  • Beverages*
  • Blood Glucose / analysis
  • Carbamates / administration & dosage
  • Carbamates / blood
  • Carbamates / pharmacokinetics*
  • Citrus paradisi*
  • Cross-Over Studies
  • Cytochrome P-450 CYP2C8
  • Genotype
  • Humans
  • Hypoglycemic Agents / administration & dosage
  • Hypoglycemic Agents / blood
  • Hypoglycemic Agents / pharmacokinetics*
  • Male
  • Piperidines / administration & dosage
  • Piperidines / blood
  • Piperidines / pharmacokinetics*
  • Polymorphism, Genetic / genetics*
  • Quinidine / analogs & derivatives
  • Quinidine / blood


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