BIOTRANSFORMATION OF IRBESARTAN IN MAN

The metabolism of irbesartan, a highly selective and potent nonpeptide angiotensin II receptor antagonist, has been investigated in humans. An aliquot of pooled urine from healthy subjects given a 50-mg oral do se of [C-14]irbesartan was added as a tracer to urine from healthy sub jects that received multiple, 900-mg nonradiolabeled doses of irbesart an, Urinary metabolites were isolated, and structures were elucidated by mass spectroscopy, proton NMR, and high-performance liquid chromato graphy (HPLC) retention times. Irbesartan and the following eight meta bolites were identified in human urine: (1) a tetrazole N-2-beta-glucu ronide conjugate of irbesartan, (2) a monohydroxylated metabolite resu lting from omega-1 oxidation of the butyl side chain, (3, 4) two diffe rent monohydroxylated metabolites resulting from oxidation of the spir ocyclopentane ring, (5) a diol resulting from omega-1 oxidation of the butyl side chain and oxidation of the spirocyclopentane ring, (6) a k eto metabolite resulting from further oxidation of the omega-1 monohyd roxy metabolite, (7) a keto-alcohol resulting from further oxidation o f the omega-1 hydroxyl of the diol, and (8) a carboxylic acid metaboli te resulting from oxidation of the terminal methyl group of the butyl side chain. Biotransformation profiles of pooled urine, feces, and pla sma samples from healthy male volunteers given doses of [C-14]irbesart an were determined by HPLC, The predominant drug-related component in plasma was irbesartan (76-88% of the plasma radioactivity). None of th e metabolites exceeded 9% of the plasma radioactivity. Radioactivity i n urine accounted for about 20% of the radiolabeled dose. In urine, ir besartan and its glucuronide each accounted for about 5 to 10% of the urinary radioactivity. The predominant metabolite in urine was the ome ga-1 hydroxylated metabolite, which constituted about 25% of the urina ry radioactivity. In feces, irbesartan was the predominant drug-relate d component (about 30% of the radioactivity), and the primary metaboli tes were monohydroxylated metabolites and the carboxylic acid metaboli te. Irbesartan and these identified metabolites constituted 90% of the recovered urinary and fecal radioactivity from human subjects given o ral doses of [C-14]irbesartan.