CYP3A4 genetic polymorphism influences repaglinide's pharmacokinetics

Pharmacology. 2010;85(6):357-64. doi: 10.1159/000302731. Epub 2010 Jun 4.

Abstract

Aim: To investigate the effects of CYP3A4 and CYP2C8 enzymes on repaglinide's pharmacokinetics in healthy Malaysian subjects.

Methods: Subjects (n = 121) received oral repaglinide (4 mg). Blood samples were taken at 0, 30, 60, 120, 180 and 240 min and serum concentrations of repaglinide were determined using high-performance liquid chromatography. Subjects were also genotyped by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) for CYP3A4*4, *5 and*18 and by an allele-specific multiplex PCR for CYP2C8*2, *3, *4 and *5 alleles.

Results: The allele frequencies of CYP2C8*1, *2, *3, *4 and *5 were 95.04, 0.40, 0.40, 0 and 4.13%, respectively. The frequencies of the CYP3A4*1, *4, *5 and *18 alleles were 97.93, 0, 0 and 2.07%, respectively. CYP2C8 and CYP3A4 genotypes were not significantly associated with repaglinide's blood glucose-lowering effect. However, the CYP3A4 genotype significantly influenced some of repaglinide's pharmacokinetics, where the mean elimination rate constant was 44.0% lower (p = 0.04) and the mean half-life was 33.8% higher (p = 0.04) in subjects with the CYP3A4*1/*18 genotype as compared to those with the normal CYP3A4*1/*1 genotype. This result confirms that CYP3A4 plays a large role in metabolizing repaglinide.

Conclusion: Genetic polymorphisms of CYP3A4, specifically CYP3A4*18, play a major role in contributing to the interindividual variability in repaglinide's pharmacokinetics.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adolescent
  • Adult
  • Aryl Hydrocarbon Hydroxylases / blood
  • Aryl Hydrocarbon Hydroxylases / genetics*
  • Asian People
  • Carbamates / administration & dosage
  • Carbamates / blood
  • Carbamates / pharmacokinetics*
  • Carbamates / pharmacology
  • Cytochrome P-450 CYP2C8
  • Cytochrome P-450 CYP3A / blood
  • Cytochrome P-450 CYP3A / genetics*
  • Genotype
  • Humans
  • Hypoglycemic Agents / administration & dosage
  • Hypoglycemic Agents / blood
  • Hypoglycemic Agents / pharmacokinetics
  • Hypoglycemic Agents / pharmacology
  • Middle Aged
  • Piperidines / administration & dosage
  • Piperidines / blood
  • Piperidines / pharmacokinetics*
  • Piperidines / pharmacology
  • Polymorphism, Genetic*
  • Young Adult

Substances

  • Carbamates
  • Hypoglycemic Agents
  • Piperidines
  • repaglinide
  • Aryl Hydrocarbon Hydroxylases
  • CYP2C8 protein, human
  • Cytochrome P-450 CYP2C8
  • Cytochrome P-450 CYP3A
  • CYP3A4 protein, human