Metabolic fate of the new angiotensin-converting enzyme inhibitor imidapril in animals. 1st communication: absorption, pharmacokinetics and excretion in rats and dogs.

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) is an ester prodrug of the angiotensin-converting enzyme (ACE) inhibitor, 6366 A (CAS 89371-44-8). Absorption, pharmacokinetics and excretion of imidapril were studied in rats and dogs after oral and intravenous administration of [N-methyl-14C]-imidapril and [N-methyl-14C]-6366 A (1 mg/kg). Following oral administration of 14C-labeled imidapril and 6366 A to rats, plasma concentrations of radioactivity were much higher after [N-methyl-14C]-imidapril dosing than after [N-methyl-14C]-6366 A dosing at all time points. Imidapril was relatively rapidly absorbed from the digestive tract and easily metabolized to the pharmacologically active 6366 A after oral dosing in the rats and dogs. Thus, imidapril proved to be an orally usable 6366 A prodrug. More than 62% and 38% of the dose were assumed to be absorbed from the gastrointestinal tract in the rats and dogs, respectively. The in situ absorption study showed that [N-methyl-14C]-imidapril was absorbed from nearly the entire rat small intestine, especially from the jejunum, but hardly absorbed from the stomach. After oral administration, peak levels of radioactivity in the plasma occurred at 1 h in rats and 30 min to 2 h in dogs. The disappearance of unchanged drug from the plasma was much faster in rats than in dogs.(ABSTRACT TRUNCATED AT 250 WORDS)