Inhibition of esterolysis of enalapril by paraoxon increases the urinary clearance in isolated perfused rat kidney.
The effect of competing elimination pathways on the metabolic and excretory clearance estimates was examined with tracer concentrations of [(3)H]enalapril, which was both metabolized and excreted by the rat kidney. Perturbation was achieved with use of the carboxylesterase inhibitor paraoxon, which inhibited [(3)H]enalapril metabolism to [(3)H]enalaprilat in rat renal S9 fraction. At 0.1, 0.5, 1, and 10 microM paraoxon, esterolysis of enalapril was inhibited by 76 +/- 7, 93 +/- 5, 96 +/- 5, and 93 +/- 6%, respectively. The lowest concentration (0.1 microM) of paraoxon was chosen for single-pass isolated perfused kidney (IPK) studies because viability was least compromised, and the sodium and glucose reabsorptive functions of the IPK remained constant. After an equilibration period (15-20 min at constant pressure, 90-100 mm Hg), perfusion of the rat kidney with [(3)H]enalapril was carried out under constant flow (8 ml/min) for 30 min in the absence and presence of paraoxon (0.1 microM). The metabolic (from 1.83 +/- 0.52 to 1.48 +/- 0.47 ml/min/g) and total renal (from 1.87 +/- 0.46 to 1. 57 +/- 0.41 ml/min/g) clearances of [(3)H]enalapril in the IPKs were decreased significantly (p <.05) in the presence of paraoxon when compared with controls. Concomitantly, the urinary clearance (from 0. 04 +/- 0.07 to 0.09 +/- 0.09 ml/min/g) and the fractional excretion (from 0.23 +/- 0.18 to 0.52 +/- 0.25) of [(3)H]enalapril doubled (p <.05). The study illustrates that a reduction in cellular metabolism of the kidney brings forth a rise in the estimate of clearance of its complimentary pathway, estimate of the excretory (urinary) clearance.
Sirianni
G L
GL
Department of Pharmacology, University of Toronto, Toronto, Ontario, Canada. pang@phm.utoronto.ca
Pang
K S
KS
D000465:Algorithms; D000806:Angiotensin-Converting Enzyme Inhibitors / Q000378:metabolism* / Q000652:urine; D000818:Animals; D002470:Cell Survival / Q000187:drug effects; D002800:Cholinesterase Inhibitors / Q000494:pharmacology*; D002855:Chromatography, Thin Layer; D004656:Enalapril / Q000378:metabolism* / Q000652:urine; D015773:Enalaprilat / Q000378:metabolism / Q000652:urine; D066298:In Vitro Techniques; D007668:Kidney / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism*; D008297:Male; D010261:Paraoxon / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D013347:Subcellular Fractions / Q000187:drug effects / Q000378:metabolism
D000806:Angiotensin-Converting Enzyme Inhibitors; D002800:Cholinesterase Inhibitors; D004656:Enalapril; D015773:Enalaprilat; D010261:Paraoxon