Drug-Drug Interaction Of Losartan And Glimepiride Metabolism By Recombinant Microsome Cyp2c9*1, 209*3, 209*13, And 2c9*16 In Vitro

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 mu M, 0.424 +/- 0.032 mu M, 2.557 +/- 0.058 mu M, and 0.667 +/- 0.039 mu M, 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 mu M) was significantly lower than with CYP2C9*1 (0.1476 +/- 0.0219 mu M) and CYP2C9*16 (0.2671 +/- 0.0456 mu M). 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 approximate to CYP2C9*3 approximate to CYP2C9*16 > CYP2C9*13 by 4 mu M losartan. No significant inhibition was observed when 0.5 mu M 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 infounation for optimizing the anti-hypertension efficacy of losartan when glimepiride is co-administered to patients.