Abstract
The effect of competing elimination pathways on the metabolic and excretory clearance estimates was examined with tracer concentrations of [3H]enalapril, which was both metabolized and excreted by the rat kidney. Perturbation was achieved with use of the carboxylesterase inhibitor paraoxon, which inhibited [3H]enalapril metabolism to [3H]enalaprilat in rat renal S9 fraction. At 0.1, 0.5, 1, and 10 μM paraoxon, esterolysis of enalapril was inhibited by 76 ± 7, 93 ± 5, 96 ± 5, and 93 ± 6%, respectively. The lowest concentration (0.1 μM) 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 [3H]enalapril was carried out under constant flow (8 ml/min) for 30 min in the absence and presence of paraoxon (0.1 μM). 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 [3H]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 [3H]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.
Footnotes
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Send reprint requests to: Dr. K. S. Pang, Faculty of Pharmacy, University of Toronto, 19 Russell Street, Toronto, Ontario, Canada M5S 2S2. E-mail: pang{at}phm.utoronto.ca
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This work was supported by the Medical Research Council of Canada (MT-15657) and the National Institutes of Health (GM-38250).
- Abbreviations used are::
- IPK
- isolated perfused rat kidney
- KHB
- Krebs-Henseleit bicarbonate
- GFR
- glomerular filtration rate
- FE
- fractional excretion
- TLC
- thin-layer chromatography
- Received July 16, 1998.
- Accepted May 4, 1999.
- The American Society for Pharmacology and Experimental Therapeutics
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