Vol. 26, Issue 5, 408-417, May 1998

Biotransformation of Irbesartan in Man

Theodore J. Chando, Donald W. Everett, Alicia D. Kahle, Anne M. Starrett, Nimish Vachharajani, Wen Chyi Shyu, Kishin J. Kripalani, and Rashmi H. Barbhaiya

Departments of Metabolism and Pharmacokinetics (T.J.C., D.W.E., N.V., W.C.S., K.J.K., R.H.B.), Analytical Research & Development (A.M.S.), and Core Resources (A.D.K.), The Bristol-Myers Squibb Pharmaceutical Research Institute

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 dose of [¹⁴C]irbesartan was added as a tracer to urine from healthy subjects that received multiple, 900-mg nonradiolabeled doses of irbesartan. Urinary metabolites were isolated, and structures were elucidated by mass spectroscopy, proton NMR, and high-performance liquid chromatography (HPLC) retention times. Irbesartan and the following eight metabolites were identified in human urine: (1) a tetrazole N²--glucuronide conjugate of irbesartan, (2) a monohydroxylated metabolite resulting from -1 oxidation of the butyl side chain, (3, 4) two different monohydroxylated metabolites resulting from oxidation of the spirocyclopentane ring, (5) a diol resulting from -1 oxidation of the butyl side chain and oxidation of the spirocyclopentane ring, (6) a keto metabolite resulting from further oxidation of the -1 monohydroxy metabolite, (7) a keto-alcohol resulting from further oxidation of the -1 hydroxyl of the diol, and (8) a carboxylic acid metabolite resulting from oxidation of the terminal methyl group of the butyl side chain. Biotransformation profiles of pooled urine, feces, and plasma samples from healthy male volunteers given doses of [¹⁴C]irbesartan were determined by HPLC. The predominant drug-related component in plasma was irbesartan (76-88% of the plasma radioactivity). None of the metabolites exceeded 9% of the plasma radioactivity. Radioactivity in urine accounted for about 20% of the radiolabeled dose. In urine, irbesartan and its glucuronide each accounted for about 5 to 10% of the urinary radioactivity. The predominant metabolite in urine was the -1 hydroxylated metabolite, which constituted about 25% of the urinary radioactivity. In feces, irbesartan was the predominant drug-related component (about 30% of the radioactivity), and the primary metabolites were monohydroxylated metabolites and the carboxylic acid metabolite. Irbesartan and these identified metabolites constituted 90% of the recovered urinary and fecal radioactivity from human subjects given oral doses of [¹⁴C]irbesartan.