Abstract

Enalaprilat (MK-422), a new and potent angiotensin- converting enzyme inhibitor, and its monoethyl ester precursor, enalapril, were studied in a single pass perfused rat liver preparation under constant perfusate flow (10 ml/min) at concentrations of 0.29-0.41 microM for 14C-enalapril and 0.01-0.015 microM for 3H- enalaprilat . During their simultaneous delivery to the same rat liver preparation, the steady state hepatic extraction ratio of 14C-enalapril was high (0.861 +/- 0.02) and 14C- enalaprilat appeared rapidly in effluent perfusate plasma. Of the enalapril dose, 22.7 +/- 6.9% appeared in bile. 14C- Enalaprilat accounted for 79% of the total radioactivity in bile (18% of dose) whereas 14C-enalapril was present only as 10% of the total (2.3% of dose). By contrast, the steady state hepatic extraction of 3H- enalaprilat was very low (0.053) and the disappearance was virtually identical to the appearance of 3H- enalaprilat in bile. These findings suggest that diffusional barrier exists for enalaprilat as the preformed metabolite, which hinders penetration into hepatocytes, and therefore, elimination. The precursor, enalapril, effectively brings enalaprilat into hepatocytes were more extensive biliary excretion of the generated metabolite takes place. This account adds to our further understanding of metabolite kinetics; in addition to the uneven distribution of enzyme system and the intrinsic clearance for metabolite formation and elimination, the presence of a diffusional barrier is another important determinant which may cause deviations between the kinetics of a generated and performed metabolite.