Impact of CYP2C9 amino acid polymorphisms on glyburide kinetics and on the insulin and glucose response in healthy volunteers

Clin Pharmacol Ther. 2002 Apr;71(4):286-96. doi: 10.1067/mcp.2002.122476.


Background: Glyburide (INN, glibenclamide) is a second-generation sulfonylurea antidiabetic agent with high potency. We hypothesized that glyburide may be a substrate of cytochrome P450 2C9 (CYP2C9), an enzyme that has two low-activity amino acid variants-Arg144Cys (CYP2C9*2) and Ile359Leu (CYP2C9*3). We explored the impact of these polymorphisms on glyburide pharmacokinetics and the effects on insulin and glucose concentrations.

Methods: Twenty-one healthy volunteers who represented all possible combinations of the two variant alleles were studied (genotypes CYP2C9*1/*1, *1/*2, *2/*2, *1/*3, *2/*3, and *3/*3 ). They received a single oral dose of 3.5 mg glyburide followed by 75 g glucose at 1, 4.5, and 8 hours after administration of glyburide. Glyburide was quantified in plasma by reversed-phase HPLC. Venous blood concentrations of glyburide, insulin, and glucose were analyzed with a population pharmacokinetic-pharmacodynamic model by use of NONMEM statistical software.

Results: Pharmacokinetics of glyburide depended significantly on CYP2C9 genotypes. In homozygous carriers of the genotype *3/*3, total oral clearance was less than half of that of the wild-type genotype *1/*1 (P <.001). Correspondingly, insulin secretion measured within 12 hours after glyburide ingestion was higher in carriers of the genotype *3/*3 compared with the other genotypes (P =.028), whereas the differences in glucose concentrations were not significant.

Conclusions: Carriers of the CYP2C9 variant *3 had decreased oral clearances of glyburide. This confirms that glyburide is metabolized by CYP2C9. Corresponding differences in insulin plasma levels indicated that dose adjustment based on CYP2C9 genotype may improve antidiabetic treatment.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Alleles
  • Amino Acids / genetics*
  • Analysis of Variance
  • Area Under Curve
  • Aryl Hydrocarbon Hydroxylases*
  • Biotransformation
  • Blood Glucose / metabolism*
  • Cytochrome P-450 CYP2C9
  • Cytochrome P-450 Enzyme System / genetics*
  • Drug Evaluation / methods
  • Drug Evaluation / statistics & numerical data
  • Genotype
  • Glyburide / blood
  • Glyburide / pharmacokinetics*
  • Humans
  • Hypoglycemic Agents / blood
  • Hypoglycemic Agents / pharmacokinetics
  • Insulin / blood*
  • Male
  • Polymorphism, Genetic / genetics*
  • Steroid 16-alpha-Hydroxylase*
  • Steroid Hydroxylases / genetics*


  • Amino Acids
  • Blood Glucose
  • Hypoglycemic Agents
  • Insulin
  • Cytochrome P-450 Enzyme System
  • Steroid Hydroxylases
  • CYP2C9 protein, human
  • Cytochrome P-450 CYP2C9
  • Aryl Hydrocarbon Hydroxylases
  • Steroid 16-alpha-Hydroxylase
  • Glyburide