Effects of CYP2C9*3 and *13 alleles on the pharmacokinetics and pharmacodynamics of glipizide in healthy Korean subjects.

Glipizide is a second-generation sulfonylurea antidiabetic drug. It is principally metabolized to inactive metabolites by genetically polymorphic CYP2C9 enzyme. In this study, we investigated the effects of CYP2C93 and 13 variant alleles on the pharmacokinetics and pharmacodynamics of glipizide. Twenty-four healthy Korean volunteers (11 subjects with CYP2C91/1, 8 subjects with CYP2C91/3, and 5 subjects with CYP2C91/13) were recruited for this study. They were administered a single oral dose of glipizide 5 mg. The plasma concentration of glipizide was quantified for pharmacokinetic analysis and plasma glucose and insulin concentrations were measured as pharmacodynamic parameters. The results represented that CYP2C93 and 13 alleles significantly affected the pharmacokinetics of glipizide. In subjects with CYP2C91/3 and CYP2C91/13 genotypes, the mean AUC were increased by 44.8% and 58.2%, respectively (both P < 0.001), compared to those of subjects with CYP2C91/1 genotype, while effects of glipizide on plasma glucose and insulin levels were not significantly different between CYP2C9 genotype groups. In conclusion, individuals carrying the defective CYP2C93 and CYP2C913 alleles have markedly elevated plasma concentrations of glipizide compared with CYP2C9*1/*1 wild-type.