CYP2C9 and OATP1B1 genetic polymorphisms affect the metabolism and transport of glimepiride and gliclazide

Sci Rep. 2018 Jul 20;8(1):10994. doi: 10.1038/s41598-018-29351-4.

Abstract

The therapeutic use of glimepiride and gliclazide shows substantial inter-individual variation in pharmacokinetics and pharmacodynamics in human populations, which might be caused by genetic differences among individuals. The aim of this study was to assess the effect of CYP2C9 and OATP1B1 genetic polymorphisms on the metabolism and transport of glimepiride and gliclazide. The uptake of glimepiride and gliclazide was measured in OATP1B1*1a, *5 and *15-HEK293T cells, and their metabolism was measured using CYP2C9*1, *2 and *3 recombinase by LC-MS. Glimepiride in OATP1B1*1a, *5 and *15-HEK293T cells had Vmax values of 155 ± 18.7, 80 ± 9.6, and 84.5 ± 8.2 pmol/min/mg, while gliclazide had Vmax values of 15.7 ± 4.6, 7.2 ± 2.5, and 8.7 ± 2.4 pmol/min/mg, respectively. The clearance of glimepiride and gliclazide in OATP1B1*5 and *15 was significantly reduced compared to the wild-type. Glimepiride in the presence of CYP2C9*1, *2 and *3 recombinase had Vmax values of 21.58 ± 7.78, 15.69 ± 5.59, and 9.17 ± 3.03 nmol/min/mg protein, while gliclazide had Vmax values of 15.73 ± 3.11, 10.53 ± 4.06, and 6.21 ± 2.94 nmol/min/mg protein, respectively. The clearance of glimepiride and gliclazide in CYP2C9*2 and *3 was significantly reduced compared to the wild-type. These findings collectively indicate that OATP1B1*5 and *15 and CYP2C9*2 and *3 have a significant effect on the transport and metabolism of glimepiride and gliclazide.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Cell Line
  • Cytochrome P-450 CYP2C9 / genetics*
  • Cytochrome P-450 CYP2C9 / pharmacology
  • Gliclazide / metabolism
  • Gliclazide / pharmacokinetics*
  • HEK293 Cells
  • Humans
  • Hypoglycemic Agents / metabolism
  • Hypoglycemic Agents / pharmacokinetics
  • Liver-Specific Organic Anion Transporter 1 / genetics*
  • Liver-Specific Organic Anion Transporter 1 / pharmacology
  • Metabolic Clearance Rate / drug effects
  • Polymorphism, Genetic / physiology*
  • Sulfonylurea Compounds / metabolism
  • Sulfonylurea Compounds / pharmacokinetics*

Substances

  • Hypoglycemic Agents
  • Liver-Specific Organic Anion Transporter 1
  • SLCO1B1 protein, human
  • Sulfonylurea Compounds
  • glimepiride
  • CYP2C9 protein, human
  • Cytochrome P-450 CYP2C9
  • Gliclazide