ABSTRACT
1. The metabolism of perindopril (non-thiol angiotensin-converting enzyme inhibitor) was studied in rat, dog and monkey after single oral and i.v. administration of 14C-perindopril, and in man after a single oral dose. 2. Six biotransformation products of perindopril from urine, faecal and plasma samples (bile only for rats) were identified. 3. The main route of biotransformation in all species is the hydrolysis of the carboxylic ethyl ester side-chain, with the formation of perindoprilate, the active metabolite. 4. A minor route of biotransformation led to the acyl glucuronides of perindopril and perindoprilate. 5. Internal dehydration of perindopril and perindoprilate into cyclic lactam structures occurs. This route of metabolism is of minor importance except in humans.
Subject(s)
Angiotensin-Converting Enzyme Inhibitors/pharmacokinetics , Indoles/pharmacokinetics , Animals , Biotransformation , Dogs , Feces/chemistry , Female , Glucuronates/metabolism , Humans , Hydrolysis , Indoles/blood , Indoles/urine , Macaca mulatta , Male , Molecular Structure , Perindopril , Rats , Rats, Inbred Strains , Species SpecificityABSTRACT
1. Adult rat hepatocytes co-cultured with rat liver epithelial cells were used to evaluate chronic cytotoxicity of a new alpha 2 agonist, oxaminozoline (S-3341-3) compared to that of clonidine. The same maximum non-toxic concentration (25 micrograms per ml of medium) was found for both drugs after a daily treatment for 12 days. 2. Oxaminozoline metabolism was analysed in short-term hepatocyte cultures. Four metabolites resulting from oxidation or hydrolysis of the parent drug were identified. Three of the metabolites were identical to those reported in vivo. The presence of an additional minor metabolite in culture may be due to the higher metabolic rate of the drug in this model system.
