Metabolic fate of the new angiotensin-converting enzyme inhibitor imidapril in animals. 5th communication: isolation and identification of metabolites of imidapril in rats, dogs, and monkeys.
The metabolism 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) was studied in rats and dogs after oral or intravenous administration of [N-methyl-14C]-imidapril or [alanine-3-14C]-imidapril, and in monkeys after oral administration of [alanine-3-14C]-imidapril. Radio-chromatographic analysis of the metabolites of imidapril from the plasma, urine, and bile of rats, dogs, or monkeys resulted in the detection of at least four metabolites. These four metabolites were isolated and characterized by high performance liquid chromatography (HPLC) and gas chromatography-mass spectrometry(GC-MS). Of these metabolites, M1 (6366 A, CAS 89371-44-8) was pharmacologically active; however, M2, M3, and M4 were inactive. There was no evidence of any glucuronides or sulfates of drug-related compounds, or of the piperazine-dione lactam type metabolites of imidapril or 6366 A in the urine of the animals used. Imidapril was metabolized by hydrolysis at the carboxylic ethyl ester side-chain to give M1, and by cleavage of the amide bond to form M2 and M3. M4 was formed by hydrolysis of M3 and/or cleavage of the amide bond of M1. Qualitatively, the same metabolites were found in all animal species tested; however, quantitatively, there were differences in the amounts of metabolites formed depending on the species.
Yamada
Y
Y
Research Laboratory of Drug Metabolism, Tanabe Seiyaku Co., Ltd., Saitama, Japan.
Ohashi
R
R
Sugawara
Y
Y
Otsuka
M
M
Takaiti
O
O
D000284:Administration, Oral; D000806:Angiotensin-Converting Enzyme Inhibitors / Q000008:administration & dosage / Q000378:metabolism* / Q000493:pharmacokinetics / Q000652:urine; D000818:Animals; D001646:Bile / Q000378:metabolism; D002851:Chromatography, High Pressure Liquid; D004285:Dogs; D008401:Gas Chromatography-Mass Spectrometry; D007093:Imidazoles / Q000008:administration & dosage / Q000378:metabolism* / Q000493:pharmacokinetics / Q000652:urine; D048289:Imidazolidines; D007275:Injections, Intravenous; D008252:Macaca fascicularis; D008297:Male; D051381:Rats; D011919:Rats, Inbred Strains
D000806:Angiotensin-Converting Enzyme Inhibitors; D007093:Imidazoles; D048289:Imidazolidines; C065166:imidapril