Vol. 31, Issue 1, 67-75, January 2003

Comparative Biotransformation of Radiolabeled [¹⁴C]Omapatrilat and Stable-labeled [¹³C₂]Omapatrilat after Oral Administration to Rats, Dogs, and Humans

Ramaswamy A. Iyer, Bimal Malhotra, Sanaullah Khan, James Mitroka, Samuel Bonacorsi, Jr., Stephen C. Waller, J. Kent Rinehart, and Kishin Kripalani

Departments of Clinical Discovery (R.A.I., S.K., J.M., K.K.), Global Regulatory Sciences (B.M.), and Discovery Chemistry (S.B., S.C.W., J.K.R.), Bristol-Myers Pharmaceutical Research Institute, Princeton, New Jersey

Omapatrilat, a novel vasopeptidase inhibitor, is under development for the treatment of hypertension and congestive heart failure. This study describes the comparative biotransformation of radiolabeled [¹⁴C]- and stable-labeled [¹³C₂]omapatrilat after administration of single oral doses to rats, dogs, and humans. The metabolites were identified by a combination of methods including reduction, hydrolysis, and comparison of high performance liquid chromatography retention times with those of the synthetic standards. Urinary metabolites were further characterized by liquid chromatography tandem mass spectrometry analysis. Prominent metabolites identified in human plasma, which were also present in rat and dog plasma, were S-methyl omapatrilat and S-2-thiomethyl-3-phenylpropionic acid. Omapatrilat accounted for only a small portion of the extractable radioactivity in plasma in all three species. A portion of the plasma radioactivity was unextractable in all three species (27-53%). The majority of unextractable radioactivity in plasma was characterized after dithiothreitol reduction to be omapatrilat and (S)-2-thio-3-phenylpropionic acid, both apparently bound to plasma proteins by reversible disulfide bonds. The major human urinary metabolites were the amine hydrolysis product, diasteromeric sulfoxide of (S)-2-thiomethyl-3-phenylpropionic acid, acyl glucuronide of S-methyl omapatrilat, and S-methyl omapatrilat. The minor metabolites were acyl glucuronide of (S)-2-thiomethyl-3-phenylpropionic acid, L-cysteine mixed disulfide of omapatrilat, diastereomers of S-methyl sulfoxide of omapatrilat, and S-methyl omapatrilat ring sulfoxide. The metabolic profiles of dog and human urine were qualitatively similar whereas rat urine showed only metabolites arising from hydrolysis of omapatrilat. Unchanged omapatrilat was not found in rat, dog, or human urine samples indicating extensive metabolism in vivo.