Association between CYP2C9 genetic polymorphism and the pharmaockinetics and pharmacodynamics of glipizide

Purpose: Glipizide, a second-generation sulfonylurea antidiabetic agent, is used for the treatment of type II diabetes mellitus. The metabolism of glipizide is mediated primarily by CYP2C9, a highly polymorphic drug-metabolizing enzyme. CYP2C9*3 and CYP2C9*13 alleles, reported to be associated with decreased CYP2C9 enzyme activity, are found in Asians including Koreans. We investigated the effects of CYP2C9 genetic polymorphism on the pharmacokinetics and pharmacodynamics of glipizide.

Methods: Twenty-four healthy subjects were selected and they were divided into two different groups according to CYP2C9 genotype, CYP2C9EM (CYP2C9*1/*1, n=11) and CYP2C9IM (CYP2C9*1/*3 and CYP2C9*1/*13, n=13). After overnight fasting, each subject received a single oral dose of 5 mg glipizide. Blood samples were collected up to 15 hr after drug intake, and the plasma concentrations of glipizide were determined by using HPLC-UV system. Pharmacodynamics of glipizide was evaluated by the measurement of plasma glucose and insulin concentration.

Results: AUC_inf of glipizide in CYP2C9IM was 1.5-fold higher than that in CYP2C9EM (3937.3 ± 502.4 ng·hr/mL and 2625.3 ± 782.3 ng·hr/mL, respectively, P<0.0001). Oral clearance of glipizide in CYP2C9IM was 37% lower than that in CYP2C9EM (1.29 ± 0.18 L/hr and 2.05 ± 0.55 L/hr, respectively, P<0.0001). However, other parameters were not significantly different between two groups. Plasma glucose and insulin concentration between two groups were also not significantly different (P>0.05).

Conclusion: CYP2C9 genetic polymorphism has a significant impact on the pharmacokinetics, but not on the pharmacodynamics of glipizide.