INTRACELLULAR AND NOT INTRALUMINAL ESTEROLYSIS OF ENALAPRIL IN KIDNEY- STUDIES WITH THE SINGLE-PASS PERFUSED NONFILTERING RAT-KIDNEY

Two possible sites of renal metabolism exist: intracellular, by enzyme s within the peritubular cells, and intraluminal, by ecto-enzymes embe dded on the brush border membrane, The esterolysis of enalapril to its dicarboxylate metabolite, enalaprilat, was studied in the isolated pe rfused, nonfiltering rat kidney preparation (NFK) and compared with th at observed for the isolated perfused rat kidney (IPK) to ascertain th e site of metabolic conversion, For the NFK, filtration was obliterate d with the high oncotic pressure (8% bovine serum albumin in plasma) a nd ligation of the ureter, thus preventing enalapril from reaching int raluminal sites by filtration, The steady-state renal plasma clearance of enalapril in the NFK was 2.0 ml/min/g, a value similar to that (2. 1 ml/min/g) observed previously for the IPK, The rate of appearance of enalaprilat, the metabolite, in venous plasma for the NFK (30 +/- 3% of the input rate of enalapril) was also comparable with that for the IPK (27 +/- 4%), Further, identification of the site of enalapril meta bolism (cellular or luminal) was aided by simulations based on physiol ogical models and parameters obtained previously on the renal handling of enalapril and enalaprilat. These parameters were optimized to matc h closely the experimental observations. The predicted total and metab olic renal clearances for the IPK or for the NFK were similar for both the ''cellular model'' and ''luminal model'': in both instances, valu es for the NFK were 54-65% of those for the IPK. By contrast, predicti ons for the venous output rate of enalaprilat (as a percent of the inp ut rate of enalapril) were different: the ''cellular model'' predicted no change in value between the NFK and the IPK, whereas metabolite ap pearance was greatly magnified for the NFK (289% that of the IPK) with luminal metabolism, The lack of difference in venous outflow of enala prilat far the NFK and IPK was more congruent with the notion of intra cellular and not intraluminal esterolysis of enalapril.