Metabolic fate of the new angiotensin-converting enzyme inhibitor imidapril in animals. 6th communication: interspecies comparison of pharmacokinetics and excretion of imidapril metabolites in rats, dogs, and monkeys
Yamada, Y.; Endo, M.; Kohno, M.; Otsuka, M.; Takaiti, O.
Arzneimittel-Forschung 42(4): 499-506
1992
ISSN/ISBN: 0004-4172 PMID: 1642673 Document Number: 698
The pharmacokinetics and excretion of the main metabolites of imidapril hydrochloride ((-)-(4S)-3-[(2S)-2-[[(1S)-1-ethyoxycarbonyl-3-phenylpropyl]amino]propionyl]-1-methyl-2-oxoimidazolidine-4-carboxylic acid hydrochloride, imidapril, TA-6366, CAS 89396-94-1) were investigated in rats, dogs, and monkeys after oral or intravenous administration of [N-methyl-14C]-imidapril and [alanine-3-14C]-imidapril. After oral administration of 14C-labeled imidapril to rats and dogs, the plasma concentrations of the pharmacologically active metabolite, 6366 A (M1, CAS 89371-44-8), reached a peak at 1-2 h in rats and at 2-6 h in dogs. The disappearance half-lives of M1 from plasma were much longer in dogs (6.3-9.3 h) than in rats (0.9-2.3 h). At the pont of peak plasma radioactivity, the major radioactive metabolites in the plasma were M2, followed by M3, M4 > in rats; in dogs, M2 and M3 followed by M1 > M4. After intravenous administration of [N-methyl-14C]-imidapril to rats and dogs, plasma levels of M1 reached a peak at the first measuring time of 5 min in rats and at about 2 h in dogs. The half-lives of plasma M1 levels were similar to those after oral dosing. At 1 h after dosing, the major metabolites in plasma were M1 followed by M2 in both rats and dogs. Irrespective of the route of administration, unchanged imidapril disappeared more rapidly from the plasma in rats than in dogs. When 14C-labeled imidapril was administered orally to rats and dogs, the main metabolites excreted in the urine up to 24 h after dosing were M2 and M4 followed by M1 in rats, and M2 followed by M3 > M1, M4 in dogs. No appreciable amounts of unchanged imidapril was detected in dogs. In monkeys given oral doses of [alanine-1-14]-imidapril, the main metabolite excreted in the urine was M4 followed by M3 > M1 > unchanged imidapril. The main biliary metabolite in rats was M1 followed by M2 > unchanged imidapril following oral doses of [N-methyl-14C]-imidapril; for the intravenous dose it was M1 followed by unchanged imidapril and M2. In summary, qualitatively, the same metabolites were found in all three species, but quantitative differences were observed among them. Additionally, there was a difference in the amounts of the metabolites formed in both the rat and dog depending on the route of administration.
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