OXIDATION OF THE ANGIOTENSIN-II RECEPTOR ANTAGONIST LOSARTAN (DUP-753) IN HUMAN LIVER-MICROSOMES - ROLE OF CYTOCHROME P4503A(4) IN FORMATION OF THE ACTIVE METABOLITE EXP3174

The oxidative metabolism of losartan (DuP 753), a novel angiotensin II receptor antagonist, by human liver microsomes and purified cytochrom e P450 (P450) enzymes, was studied. The primary route of metabolism of losartan is by oxidation of the C-5-hydroxymethyl to the carboxylic a cid (EXP3174), which is an active metabolite of losartan. When microso mes prepared from different human liver samples were compared, EXP3174 formation activity was well correlated (r(2) = 0.93) with nifedipine oxidation (a marker of P4503A4), but not with markers for other human liver P450s. Microsomal oxidation of losartan to EXP3174 was markedly inhibited by ges-todene and ketoconazole, selective inhibitors of P450 3A enzymes, but not by any of several other P450 inhibitors. Antibodie s raised against P4503A4 could inhibit most of the oxidation of losart an to EXP3174 in a microsomal sample having high catalytic activity, b ut antibodies recognizing other P450s had no effect. The oxidation of losartan to EXP3174 was catalyzed by purified human liver microsomal P 4503A4 and by purified bacterial recombinant P4503A4, These results pr ovide evidence that P4503A4 (and possibly other P4503A enzymes) play a major role in the formation of an active metabolite EXP3174.