Metabolic Fate of Quinapril Hydrochloride (I). Absorption, Distribution, Metabolism and Excretion of 14C-Quinapril Hydrochloride in Rats.

Abstract

The metabolism and disposition of 14C-quinapril hydrochloride were studied in rats. The compound was mainly absorbed from the small intestine. The extent of absorption was estimated to be between 50 and 65% after an oral dose of 3 mg/ kg in fasting male rats. The plasma level of radioactivity reached a maximum at 0.5 hour, and the terminal half-life was 29.6 hours. Peak levels in plasma (Cmax) and the areas under the plasma concentration-time curve (AUC) were proportional to the dose between 1 and 30 mg/kg. In non-fasting condition Cmax decreased, but AUC did not alter. No sex-related differences were observed in pharmacokinetic parameters. High levels of radioactivity were observed in the liver, plasma, kidney, blood and the lung at 0.5 hour after the administration and the levels rapidly decreased in all tissues studied. Radioactivity was slightly detected only in the lung, liver and the kidney at 72 hours after the administration. Similar distribution characteristics were observed with the whole body autoradiograms. Residual radioactivity accounted for 0.1% in the carcasses at 120 hours after the administration. Binding extent of radioactivity to plasma proteins was between 95 and 97%. Radioactivity in plasma was hardly transferred to the blood cells. Quinaprilat, an active metabolite, was mainly detected in the plasma, urine, feces and the bile, but quinapril and other metabolites were hardly detected. Within 120 hours after oral administration of 14C-quinapril hydrochloride at a dose of 3 mg/kg to male rats, the urinary and fecal excretion of radioactivity were 18.8 and 78.6%, respectively. The excretion of radioactivity in female rats was similar to that in male rats. Within 48 hours after oral administration to bile-duct cannulated male rats, biliary excretion was 43%. Twenty two percents of radioactivity excreted in the bile was reabsorbed from the intestine.