METABOLIC-FATE OF THE NEW ANGIOTENSIN-CONVERTING ENZYME-INHIBITOR IMIDAPRIL IN ANIMALS .7. INVITRO METABOLISM

In order to clarify the sites of metabolism and the metabolizing enzymes 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), metabolism studies were carried out using rat, dog, monkey, and human plasma and rat tissue homogenates. After incubating with the various plasma samples, imidapril was mainly metabolized to the pharmacologically active metabolite, 6366 A (M1, CAS 893 71-44-8), in rat plasma; on the other hand, the ester bond of imidapril was not hydrolyzed in dog, monkey and human plasma. Imidapril was metabolized to M1, M2, M3, and M4 in all rat tissue homogenates tested. Aside from the above metabolites, no other metabolites were detected. The metabolic activity of imidapril to M1 was the highest in the liver followed by the kidney and lung; however, it was low in other tissue homogenates. From the results of experiments using certain esterase inhibitors, it has been concluded that the metabolic conversion of imidapril to M1 is mainly due to a carboxylesterase (B-esterase). In contrast, the metabolic activity of imidapril to M2 and M3 (or M4) was highest in the kidney and small intestine while low in other tissues. From the experiments using certain enzyme inhibitors, it has been found that an acetylesterase (C-esterase) is largely involved in the metabolism of imidapril into M2 and M3. These results indicate that the metabolic conversion of imidapril into M1 is performed by a carboxylesterase mainly in the liver and kidney; the metabolism to M2 and M3 occurs mainly in the small intestine and partly in the kidney by an acetylesterase.