Combined recirculation of the rat liver and kidney: studies with enalapril and enalaprilat.

Combined recirculation of the rat liver (L) and kidney (IPK) at 10 ml min-1 per organ (LK) was developed to examine the hepatorenal handling of the precursor-metabolite pair: [14C]-enalapril and [3H]enalaprilat. Loading doses followed by constant infusion of [14C]enalapril and preformed [3H]enalaprilat to the reservoirs of the IPK or the LK preparation was used to achieve steady state conditions. In both organs, enalapril was mostly metabolized to its dicarboxylic acid metabolite, enalaprilat, which was excreted unchanged. At steady state, the fractional excretion for [14C]enalapril (FE = 0.45 to 0.48) and preformed [3H]enalaprilat (FE[pmi] = 1.1) were constant and similar for both the IPK and LK. The additivity of clearance was demonstrated in the LK preparation, namely, the total clearance of enalapril was the sum of its hepatic and renal clearances. However, the apparent fractional excretion for formed [14C]enalaprilat, FE(mi) and the apparent urinary clearance were time-dependent and higher than the corresponding values for preformed [3H]enalaprilat in both the IPK and LK. The FE(mi) and urinary clearance values further differed between the IPK and LK. Biliary clearance of formed vs. preformed enalaprilat displayed the same discrepant trends as observed for FE(mi) vs. FE(pmi) for the LK. These observations on the time-dependent and variable excretory clearance (urinary or biliary) of the formed metabolite vs. the constant, and much reduced, excretory clearance of the preformed metabolite are due to dual contributions to formed metabolite excretion: the nascently formed, intracellular metabolite which immediately underwent excretion and the formed metabolite which reentered the circulation, behaved as a preformed species. When data for the IPK and LK preparations were modeled with a physiological model with parameters previously reported for the L and IPK, all data, including metabolite excretory clearances, were well predicted. Model simulations revealed that the apparent FE(mi) differed between the LK and IPK preparations when the liver was present as an additional metabolite formation organ; the apparent excretory (urinary or biliary) clearance of the formed metabolite was further modulated by the volume of distribution of the metabolite, which altered levels of the formed, circulating metabolite.