In vitro inhibition screening of human hepatic P-450 enzymes by five angiotensin-II receptor antagonists

Objective: Metabolic interactions at the level of drug-metabolising enzymes are important for drug therapy. We investigated potential interactions of losartan, irbesartan, valsartan, eprosartan and candesartan with cytochrome P-450 (CYP) enzymes in human liver microsomes. Methods: In incubations with human liver microsomes in vitro, the inhibitor y potency of angiotensin-II receptor antagonists (sartans) on CYP-specific model activities were compared by measuring the IC50 and, with respect to m ore potent inhibition, K-i values. Results: None of the five sartans inhibited CYP2A6-, CYP2D6- or CYP2E1-asso ciated activities (coumarin 7-hydroxylation, dextromethorphan O-demethylati on and chlorzoxazone 6-hydroxylation, respectively) to any significant exte nt. Losartan and irbesartan inhibited the CYP2C9-associated tolbutamide met hylhydroxylation more potently (K-i values 4.1 mu M and 24.5 mu M), than va lsartan, candesartan or eprosartan (K-i values 135 mu M, 155 mu M and > 100 0 mu M, respectively). Losartan and irbesartan inhibited CYP1A2- and CYP3A4 -associated activities (ethoxyresorufin O-deethylation and testosterone 6 b eta-hydroxylation) with relatively weak affinities (IC50 values between 200 mu M and 500 mu M). CYP2C19-associated S-mephenytoin 4'-hydroxylation acti vity was inhibited by losartan (IC50 value 138 mu M) and much less or not a t all by the other sartans tested. Conclusion: All sartans except eprosartan have at least some affinity for C YP2C9, but only losartan has an affinity for CYP2C19. Losartan and irbesart an have modest affinity for CYP1A2 and CYP3A4. This would suggest that the theoretical potential for drug interactions is likely to be quite low, with the possible exceptions of losartan and irbesartan for CYP2C9. Based on th ese findings, further studies on the interaction potential of losartan and irbesartan are warranted.