PHARMACOKINETICS OF RU44403, AN ACTIVE FORM OF NEWLY DEVELOPED ANGIOTENSIN-CONVERTING ENZYME-INHIBITOR (RU44570) IN THE RAT

Trandolapril (RU44570) is an ethyl ester prodrug of trandolprilat (RU4 4403) having angiotensin I-converting enzyme (ACE) inhibitory activity . Disposition of RU44403 was investigated by oral or intravenous admin istration of RU44570 (0.1, 1, and 3 mg/kg po or 1 mg/kg iv) and RU4440 3 (0.94 mg/kg po) 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 trans formed to RU44403, giving maximum plasma concentration within 0.5 hr. Regardless of both dose level and route of administration, almost simi lar plasma concentrations of RU44403 were observed in the terminal pha se 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 pc and 63.52 hr for 1 mg/kg iv, respectively. Furthermore, oral AUC(0-infinity) of 0.1 mg/kg RU44403 was not dose proportional, suggesting nonlinear pha rmacokinetic profile. To elucidate the factors causing the nonlinear d isposition, 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 compartme nt. 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 compar able with an inhibitor constant of RU44403 to ACE in plasma that was o btained by Henderson's plot for a kinetic analysis of the tight bindin g of an enzyme and inhibitor. From these results, nonlinear dispositio n and slow elimination of RU44403 in the terminal phase was considered to be attributable to its specific and tight binding to ACE.