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 enzymes within the peritubular cells, and intraluminal, by ecto-enzymes embedded on the brush border membrane. The esterolysis of enalapril to its dicarboxylate metabolite, enalaprilat, was studied in the isolated perfused, nonfiltering rat kidney preparation (NFK) and compared with that observed for the isolated perfused rat kidney (IPK) to ascertain the site of metabolic conversion. For the NFK, filtration was obliterated with the high oncotic pressure (8% bovine serum albumin in plasma) and ligation of the ureter, thus preventing enalapril from reaching intraluminal 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 metabolism (cellular or luminal) was aided by simulations based on physiological models and parameters obtained previously on the renal handling of enalapril and enalaprilat. These parameters were optimized to match closely the experimental observations. The predicted total and metabolic renal clearances for the IPK or for the NFK were similar for both the "cellular model" and "luminal model": in both instances, values for the NFK were 59-65% of those for the IPK. By contrast, predictions for the venous output rate of enalaprilat (as a percent of the input rate of enalapril) were different: the "cellular model" predicted no change in value between the NFK and the IPK, whereas metabolite appearance was greatly magnified for the NFK (289% that of the IPK) with luminal metabolism. The lack of difference in venous outflow of enalaprilat for the NFK and IPK was more congruent with the notion of intracellular and not intraluminal esterolysis of enalapril.
Sirianni
G L
GL
Department of Pharmacology, University of Toronto, Ontario, Canada.
Pang
K S
KS
D000806:Angiotensin-Converting Enzyme Inhibitors / Q000378:metabolism*; D000818:Animals; D004656:Enalapril / Q000378:metabolism*; D006868:Hydrolysis; D066298:In Vitro Techniques; D007668:Kidney / Q000378:metabolism*; D008297:Male; D008954:Models, Biological; D010477:Perfusion; D051381:Rats; D017207:Rats, Sprague-Dawley
D000806:Angiotensin-Converting Enzyme Inhibitors; D004656:Enalapril