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 handli ng of the precursor-metabolite pair: [C-14]-enalapril and [H-3]enalapr ilat. Loading doses followed by constant infusion of [C-14]enalapril a nd preformed [H-3]enalaprilat to the reservoirs of the IPK or the LK p reparation 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 frac tional excretion for [C-14]enalapril (FE=0.45 to 0.48) and preformed [ H-3]enalaprilat (FE{pmi}=1.1) were constant and similar for both the I PK and LK. The additivity of clearance was demonstrated in the LK prep aration, namely, the total clearance of enalapril was the sum of its h epatic and renal clearances. However, the apparent fractional excretio n for formed [C-14]enalaprilat, FE{mi} and the apparent urinary cleara nce were time-dependent and higher than the corresponding values for p reformed [H-3]enalaprilat in both the IPK and LK. The FE{mi} and urina ry clearance values further differed between the IPK and LK. Biliary c learance for formed vs. preformed enalaprilat displayed the same discr epant trends as observed for FE{mi} vs. FE{pmi} for the LK. These obse rvations on the time-dependent and variable excretory clearance (urina ry or biliary) of the formed metabolite vs. the constant, and much red uced, excretory clearance of the preformed metabolite are due to dual contributions to formed metabolite excretion: the nascently formed, in tracellular metabolite which immediately underwent excretion and the f ormed metabolite which reentered the circulation, behaved as a preform ed species. When data for the IPK and LK preparations were modeled wit h a physiological model with parameters previously reported for the L and IPK, all data, including metabolite excretory clearances, were wel l predicted. Model simulations revealed that the apparent FE{mi} diffe red between the LK and IPK preparations when the liver was present as an additional metabolite formation organ; the apparent excretory (urin ary or biliary) clearance of formed metabolite was further modulated b y the volume of distribution of the metabolite, which altered levels o f the formed, circulating metabolite.