In vitro inhibition screening of human hepatic P450 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 P450 (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, Ki 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 (Ki values 4.1 microM and 24.5 microM), than valsartan, candesartan or eprosartan (Ki values 135 microM, 155 microM and > 1000 microM, respectively). Losartan and irbesartan inhibited CYP1A2- and CYP3A4-associated activities (ethoxyresorufin O-deethylation and testosterone 6beta-hydroxylation) with relatively weak affinities (IC50 values between 200 microM and 500 microM). CYP2C1OFF S-mephenytoin 4'-hydroxylation activity was inhibited by losartan (IC50 value 138 microM) and much less or not at all by the other sartans tested.


CONCLUSIONS
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.
Taavitsainen
P
P
Department of Pharmacology and Toxicology, University of Oulu, Finland. paivi.taavitsainen@oulu.fi
Kiukaanniemi
K
K
Pelkonen
O
O
D000179:Acrylates / Q000378:metabolism; D057911:Angiotensin Receptor Antagonists; D000959:Antihypertensive Agents / Q000378:metabolism*; D001562:Benzimidazoles / Q000378:metabolism; D001713:Biphenyl Compounds / Q000378:metabolism; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism*; D004347:Drug Interactions; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006801:Humans; D007093:Imidazoles / Q000378:metabolism; D066298:In Vitro Techniques; D020128:Inhibitory Concentration 50; D000077405:Irbesartan; D019808:Losartan / Q000378:metabolism; D008862:Microsomes, Liver / Q000201:enzymology / Q000378:metabolism; D020033:Protein Isoforms / Q000378:metabolism; D013777:Tetrazoles / Q000378:metabolism; D013876:Thiophenes; D014633:Valine / Q000031:analogs & derivatives* / Q000378:metabolism; D000068756:Valsartan
D000179:Acrylates; D057911:Angiotensin Receptor Antagonists; D000959:Antihypertensive Agents; D001562:Benzimidazoles; D001713:Biphenyl Compounds; D004791:Enzyme Inhibitors; D007093:Imidazoles; D020033:Protein Isoforms; D013777:Tetrazoles; D013876:Thiophenes; C068373:eprosartan; D000068756:Valsartan; D003577:Cytochrome P-450 Enzyme System; D014633:Valine; D000077405:Irbesartan; D019808:Losartan; C081643:candesartan