Drug-drug interaction of losartan and glimepiride metabolism by recombinant microsome CYP2C9*1, 2C9*3, 2C9*13, and 2C9*16 in vitro

Int J Clin Pharmacol Ther. 2014 Sep;52(9):732-8. doi: 10.5414/CP202071.

Abstract

Objective: Co-administration of anti-hypertension and anti-diabetic drugs is common in clinical settings.

Methods: In this study, we characterized the drug-drug interactions of losartan (LOS) and glimepiride (GLP) using recombinant cytochrome P450 (CYP) 2C9 enzymes (CYP2C9*1, CYP2C9*3, CYP2C9*13, and CYP2C9*16).

Results: Metabolism of losartan by recombinant CYP2C9* 1, CYP2C9*3, CYP2C9*13, and CYP2C9* 16 was inhibited by glimepiride competitively with IC50 values of 0.669 ± 0.055 µM, 0.424 ± 0.032 µM, 2.557 ± 0.058 µM, and 0.667 ± 0.039 µM, respectively. The inhibitory effect of glimepiride on losartan metabolism by CYP2C9*13 was marginal. The apparent Ki value of glimepiride with CYP2C9*3 (0.0416 ± 0.0059 µM) was significantly lower than with CYP2C9*1 (0.1476 ± 0.0219 µM) and CYP2C9*16 (0.2671 ± 0.0456 µM). On the other hand, losartan weakly inhibited the hydroxylation of glimepiride by P450 2C9 enzymes competitively. The potencies for inhibition of glimepiride hydroxylation were determined to be CYP2C9*1~CYP2C9*3~CYP2C9*16 > CYP2C9*13 by 4 µM losartan. No significant inhibition was observed when 0.5 µM losartan was used.

Conclusions: Given these results, the potential inhibition of losartan metabolism by CYP2C9*3, CYP2C9*13, and CYP2C9*16 in vivo by glimepiride deserves further investigation. These results may provide valuable information for optimizing the anti-hypertension efficacy of losartan when glimepiride is co-administered to patients.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Angiotensin II Type 1 Receptor Blockers / adverse effects
  • Angiotensin II Type 1 Receptor Blockers / metabolism*
  • Aryl Hydrocarbon Hydroxylases / genetics
  • Aryl Hydrocarbon Hydroxylases / metabolism*
  • Biotransformation
  • Cytochrome P-450 CYP2C9
  • Drug Interactions
  • Humans
  • Hydroxylation
  • Hypoglycemic Agents / adverse effects
  • Hypoglycemic Agents / metabolism*
  • Kinetics
  • Losartan / adverse effects
  • Losartan / metabolism*
  • Microsomes / enzymology*
  • Oxidation-Reduction
  • Pharmacogenetics
  • Phenotype
  • Polymorphism, Genetic*
  • Recombinant Proteins / metabolism
  • Risk Assessment
  • Risk Factors
  • Sulfonylurea Compounds / adverse effects
  • Sulfonylurea Compounds / metabolism*

Substances

  • Angiotensin II Type 1 Receptor Blockers
  • Hypoglycemic Agents
  • Recombinant Proteins
  • Sulfonylurea Compounds
  • glimepiride
  • CYP2C9 protein, human
  • Cytochrome P-450 CYP2C9
  • Aryl Hydrocarbon Hydroxylases
  • Losartan