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

摘要

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.