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

• Published in: European journal of clinical pharmacology 2000-05, Vol.56 (2), p.135-140
• Main Authors: Taavitsainen, P., Kiukaanniemi, K., Pelkonen, O.
• Format: Article
• Language: English
• Subjects: Drug therapy; Enzymes; Studies
• ISSN: 0031-6970; 1432-1041
• DOI: 10.1007/s002280050731

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 ^sub 450^ (CYP) enzymes in human liver microsomes. Methods: In incubations with human liver microsomes in vitro, the inhibitory potency of angiotensin-II receptor antagonists (sartans) on CYP-specific model activities were compared by measuring the IC^sub 50^ and, with respect to more potent inhibition, K ^sub i^ values. Results: None of the five sartans inhibited CYP2A6-, CYP2D6- or CYP2E1-associated activities (coumarin 7-hydroxylation, dextromethorphan O-demethylation and chlorzoxazone 6-hydroxylation, respectively) to any significant extent. Losartan and irbesartan inhibited the CYP2C9-associated tolbutamide methylhydroxylation more potently (K ^sub i^ values 4.1μM and 24.5μM), than valsartan, candesartan or eprosartan (K ^sub i^ values 135μM, 155μM and >1000μM, respectively). Losartan and irbesartan inhibited CYP1A2- and CYP3A4-associated activities (ethoxyresorufin O-deethylation and testosterone 6β-hydroxylation) with relatively weak affinities (IC^sub 50^ values between 200μM and 500μM). CYP2C19-associated S-mephenytoin 4'-hydroxylation activity was inhibited by losartan (IC^sub 50^ value 138μM) and much less or not at all by the other sartans tested. Conclusion: All sartans except eprosartan have at least some affinity for CYP2C9, but only losartan has an affinity for CYP2C19. Losartan and irbesartan 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 these findings, further studies on the interaction potential of losartan and irbesartan are warranted.[PUBLICATION ABSTRACT]