DISPOSITION AND METABOLISM OF THE ANGIOTENSIN-CONVERTING ENZYME-INHIBITOR [4S-[4-ALPHA, 7-ALPHA, (R-STAR), 12B-BETA]]-7-[S-(1-ETHOXYCARBONYL-3-PHENYLPROPYL)AMINO]-1,2,3,4,6,7,8,12B-OCTAHYDRO-6-OXO-PYRIDO[2,1-A][2] BENZAZEPINE-4-CARBOXYLIC ACID IN MONKEYS AND DOGS

[4S-[4-alpha, 7-alpha, (R*), 12b-beta]]-7-[S-(1-ethoxycarbonyl-3-phenylpropyl)amino]-1,2,3,4,6,7,8,12b-octahydro-6-oxo-pyrido[2,1-][2]benzazepine-4-carboxylic acid (MDL 27,210) is the ethyl ester prodrug of a potent angiotensin-converting enzyme inhibitor, MDL 27,088. After a single dose of [C-14]MDL 27,210 (3 mg/kg iv), MDL 27,210 was rapidly eliminated from the plasma of monkeys and dogs with a terminal half-life of approximately 0.3 hr. The steady-state volume of distribution was 0.15 liter/kg in dogs and 0.28 liter/kg in monkeys. Monkeys excreted 52% of the C-14 dose in the feces and 41% in the urine; dogs excreted 80% of the C-14 dose in the feces and 14% in the urine. The presence of a large fraction of the C-14 dose in the feces of both species following iv administration suggests that significant biliary excretion occurred. MDL 27,210 administered iv to monkeys and dogs was rapidly and extensively ( > 99.9%) metabolized, primarily to its diacid metabolite, MDL 27,088. The half-life of MDL 27,088 was 2.2 hr in dogs and 3.6 hr in monkeys.