Abstract

Trandolapril (RU44570) is an ethyl ester prodrug of trandolprilat (RU44403) having angiotensin I-converting enzyme (ACE) inhibitory activity. Disposition of RU44403 was investigated by oral or intravenous administration of RU44570 (0.1, 1, and 3 mg/kg p.o. or 1 mg/kg i.v.) and RU44403 (0.94 mg/kg p.o.) to rats. Orally dosed RU44403 was scarcely absorbed from the gastrointestinal tract (3% of dose), whereas its prodrug was found to be rapidly absorbed (32.1-45.7% of dose) and completely transformed to RU44403, giving maximum plasma concentration within 0.5 hr. Regardless of both dose level and route of administration, almost similar plasma concentrations of RU44403 were observed in the terminal phase following doses of RU44570, resulting in prolonged elimination half-life, 89.01, 63.29, and 62.64 hr for 0.1, 1, and 3 mg/kg p.o. and 63.52 hr for 1 mg/kg i.v., respectively. Furthermore, oral AUC0-infinity of 0.1 mg/kg RU44403 was not dose proportional, suggesting nonlinear pharmacokinetic profile. To elucidate the factors causing the nonlinear disposition, a dissociation constant of the active metabolite in plasma was determined using a one-compartment model in which free RU44403 in plasma was the sole form available for elimination from the compartment. The value of the constant was 0.024 nM, which was closely similar to that of the high-affinity binding site of plasma protein determined by the ultrafiltration method in vitro. Also, both values were comparable with an inhibitor constant of RU44403 to ACE in plasma that was obtained by Henderson's plot for a kinetic analysis of the tight binding of an enzyme and inhibitor.(ABSTRACT TRUNCATED AT 250 WORDS)