Oral bioavailability and disposition of [C-14]omapatrilat in healthy subjects

The objective of this study was to determine the absolute oral bioavailabil ity and disposition of omapatrilat. This single-dose, randomized, crossover study of 20 mg intravenous and 50 ma oral [C-14]omapatrilat was conducted in 12 healthy male subjects to determine the disposition and oral bioavaila bility of omapatrilat, an orally active vasopeptidase inhibitor. Blood samp les were collected up to 120 hours, and the excreta were collected over 168 hours postdose. Plasma concentrations of omapatrilat were determined by a validated LC/MS/MS procedure. Radioactivity in blood, Plasma, urine, and fe ces was determined by liquid scintillation counting. Urinary excretion of r adioactivity averaged 80% and 64% of intravenous and oral doses, respective ly; < 1 % of oral dose was excreted unchanged in urine. The absolute oral b ioavailability of omapatrilat averaged 31 %. Total body clearance of omapat rilat (80 L/h) exceeded liver plasma flow. Apparent steady-state volume of distribution of omapatrilat (21 L/kg) was extremely high compared with tota l body water. Omapatrilat undergoes substantial presystemic first-pass meta bolism after oral administration. Omapatrilat is eliminated primarily by me tabolism, and its metabolites are eliminated primarily in urine. Extrahepat ic organs may be involved in the elimination of omapatrilat. Plasma concent rations of omapatrilat exhibit a prolonged terminal elimination phase, whic h represents elimination from a deep compartment. (C) 2001 the American Col lege of Clinical Pharmacology.