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.
The pharmacokinetics and excretion of the main metabolites of imidapril hydrochloride ((-)-(4S)-3-[(2S)-2-[[(1S)-1-ethoxycarbonyl-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 point of peak plasma radioactivity, the major radioactive metabolites in the plasma were M2, followed by M3, M4 greater than M1 in rats; in dogs, M2 and M3 followed by M1 greater than 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.(ABSTRACT TRUNCATED AT 250 WORDS)
Yamada
Y
Y
Research Laboratory of Drug Metabolism, Tanabe Seiyaku Co., Ltd., Saitama, Japan.
Endo
M
M
Kohno
M
M
Otsuka
M
M
Takaiti
O
O
D000284:Administration, Oral; D000806:Angiotensin-Converting Enzyme Inhibitors / Q000008:administration & dosage / Q000493:pharmacokinetics*; D000818:Animals; D001646:Bile / Q000378:metabolism; D002851:Chromatography, High Pressure Liquid; D004285:Dogs; D005243:Feces / Q000737:chemistry; D005260:Female; D006207:Half-Life; D007093:Imidazoles / Q000008:administration & dosage / Q000493:pharmacokinetics*; D048289:Imidazolidines; D007275:Injections, Intravenous; D008252:Macaca fascicularis; D008297:Male; D051381:Rats; D011919:Rats, Inbred Strains; D013045:Species Specificity
D000806:Angiotensin-Converting Enzyme Inhibitors; D007093:Imidazoles; D048289:Imidazolidines; C065166:imidapril