caa a22 4500 475819098 CHVBK 20180406123817.0 cr unu---uuuuu 170329e20000501xx s 000 0 eng 10.1007/s002280050731 doi (NATIONALLICENCE)springer-10.1007/s002280050731 In vitro inhibition screening of human hepatic P 450 enzymes by five angiotensin-II receptor antagonists [Elektronische Daten] [P. Taavitsainen, K. Kiukaanniemi, O. Pelkonen] 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 inhibitory potency of angiotensin-II receptor antagonists (sartans) on CYP-specific model activities were compared by measuring the IC50 and, with respect to more potent inhibition, K 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 i values 4.1 μM and 24.5 μM), than valsartan, candesartan or eprosartan (K i values 135 μM, 155 μM and >1000 μM, respectively). Losartan and irbesartan inhibited CYP1A2- and CYP3A4-associated activities (ethoxyresorufin O-deethylation and testosterone 6β-hydroxylation) with relatively weak affinities (IC50 values between 200 μM and 500 μM). CYP2C19-associated S-mephenytoin 4′-hydroxylation activity was inhibited by losartan (IC50 value 138 μM) 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. Springer-Verlag Berlin Heidelberg, 2000 Key words CYP nationallicence Inhibitory interactions nationallicence Sartans nationallicence Taavitsainen P. Department of Pharmacology and Toxicology, POB 5000, FIN-90014, University of Oulu, Finland e-mail: paivi.taavitsainen@oulu.fi Tel.: +358-8-5375255; Fax: +358-8-5375247, FI aut Kiukaanniemi K. Department of Pharmacology and Toxicology, POB 5000, FIN-90014, University of Oulu, Finland e-mail: paivi.taavitsainen@oulu.fi Tel.: +358-8-5375255; Fax: +358-8-5375247, FI aut Pelkonen O. Department of Pharmacology and Toxicology, POB 5000, FIN-90014, University of Oulu, Finland e-mail: paivi.taavitsainen@oulu.fi Tel.: +358-8-5375255; Fax: +358-8-5375247, FI aut https://doi.org/10.1007/s002280050731 text/html Onlinezugriff via DOI 1 research-article jats NATIONALLICENCE 856 40 https://doi.org/10.1007/s002280050731 text/html Onlinezugriff via DOI NATIONALLICENCE 700 1- Taavitsainen P. Department of Pharmacology and Toxicology, POB 5000, FIN-90014, University of Oulu, Finland e-mail: paivi.taavitsainen@oulu.fi Tel.: +358-8-5375255; Fax: +358-8-5375247, FI aut NATIONALLICENCE 700 1- Kiukaanniemi K. Department of Pharmacology and Toxicology, POB 5000, FIN-90014, University of Oulu, Finland e-mail: paivi.taavitsainen@oulu.fi Tel.: +358-8-5375255; Fax: +358-8-5375247, FI aut NATIONALLICENCE 700 1- Pelkonen O. Department of Pharmacology and Toxicology, POB 5000, FIN-90014, University of Oulu, Finland e-mail: paivi.taavitsainen@oulu.fi Tel.: +358-8-5375255; Fax: +358-8-5375247, FI aut Metadata rights reserved Springer special CC-BY-NC licence nationallicence BK010053 XK010053 XK010000 NATIONALLICENCE NATIONALLICENCE NL-springer