Disposition and metabolism of the novel antihypertensive agent alacepril in rats.

Disposition and metabolism of 1-[(S)-3-acetylthio-2-methylpropanoyl]-L-prolyl-L-phenylalanine (alacepril, DU-1219) in rats were studied and compared to those of 1-[(S)-3-mercapto-2-methylpropanoyl]-L-proline (captopril), using 14C-labeled compounds. Some tissue homogenates and plasma of rats were incubated in vitro with [14C]alacepril or [14C]captopril at the concentration of 50 nmol/ml. For in vivo studies, radioactive agents were orally or intravenously administered to rats in doses of 46 mumol/kg (18.7 and 10 mg/kg for alacepril and captopril, respectively) or 460 mumol/kg. In vitro studies revealed that [14C]alacepril is converted to captopril via desacetyl-alacepril (DU-1227) in the liver, kidney and intestine homogenates, but not in the lung homogenate and plasma where deacetylation alone occurred. DU-1227 and captopril formed were found to be partly bound with endogenous -SH compounds i.e. cysteine, glutathione and probably, protein. 1 h after oral administration of [14C]alacepril, plasma levels of total radioactivity reached a maximum of 8 nmol/ml and disappeared with t1/2 of 2.6 h. [14C]Captopril radioactivity was maximum (13 nmol/ml) at 40 min with the disappearance t1/2 of 1.9 h. Similarly to total radioactivity, levels of radioactivity unbound and bound to plasma protein after [14C]alacepril were lower at maximum and disappeared more slowly than those after [14C]captopril. After oral administration of [14C]alacepril, DU-1227, captopril and mixed disulfides of captopril with cysteine and glutathione were detected in the plasma unbound fraction. The three metabolites except for DU-1227 were commonly detected after [14C]captopril.(ABSTRACT TRUNCATED AT 250 WORDS)