Abstract
Renal effects of acetaminophen (APAP) were studied in rats pretreated with probenecid to analyze whether acute APAP-induced nephrotoxicity could be related to a probenecid-sensitive transport system for APAP or its S-derived conjugates. The administration of probenecid (200 mg/kg b.wt. i.p.) 30 min before APAP administration (1000 mg/kg b.wt. i.p.) improved urine flow rate and protected against the alterations on glomerular filtration rate and urea and creatinine plasma levels induced by APAP. Fewer epithelial cells and granular casts and a decrease in the urinary excretion of protein and glucose were observed in rats pretreated with probenecid. Probenecid pretreatment promoted an elevation in the urinary 16-hr excretion of APAP and a diminution in the plasma levels attained by APAP. These results suggest that protection afforded by probenecid in vivo could be a consequence of the inhibition of APAPS-conjugate renal uptake and/or an increase in APAP renal clearance. The effects of APAP in presence of probenecid were studied with the isolated perfused kidney model. Perfusion with probenecid (0.1 mM) before APAP (10 mM) did not change APAP direct renal effects, APAP urinary excretion, or APAP renal clearance relative to glomerular filtration rate. Our results suggest that protection afforded by probenecid in vivo could be the result of the inhibition of the uptake of nephrotoxic APAP metabolites and/or a diuresis-induced enhanced APAP renal excretion.
Footnotes
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Send reprint requests to: Dr. M. Mónica Elı́as, Farmacologı́a, Facultad de Ciencias Bioquı́micas y Farmacéuticas, Universidad Nacional de Rosario, Suipacha 531, 2000 Rosario, República Argentina.
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↵1 This work was supported by grants from Consejo Nacional de Investigaciones Cientı́ficas y Técnicas (CONICET) and Consejo de Investigaciones de la Universidad Nacional de Rosario (CIUNR) (L.T.).
- Abbreviations:
- APAP
- acetaminophen
- IPK
- isolated perfused kidney
- GSH
- glutathione
- GFR
- glomerular filtration rate
- γGT
- γ-glutamyl transpeptidase
- PAH
- p-aminohippuric acid
- CPAH
- clearance of p-aminohippuric acid
- CAPAP
- clearance of acetaminophen
- FENa
- fractional excretion of sodium
- FEH2O
- fractional excretion of water
- FEGlu
- fractional excretion of glucose
- UFR
- urine flow rate
- PROB
- probenecid
- PF
- perfusion flow
- PP
- perfusion pressure
- Received May 27, 1997.
- Accepted October 27, 1997.
- The American Society for Pharmacology and Experimental Therapeutics
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