Effects of drug-metabolizing enzyme inducers on cephaloridine toxicity in Fischer 344 rats.
High doses of cephaloridine produce necrosis of renal proximal tubular cells and this nephrotoxicity has been shown to be reduced by piperonyl butoxide (a mixed-function oxidase inhibitor) in rats and rabbits, and potentiated by phenobarbital (a mixed-function oxidase inducer) in rabbits but not rats. Phenobarbital is known to increase rabbit but not rat renal mixed-function oxidase activities; however, several other compounds such as polybrominated biphenyls (PBB), trans-stilbene oxide (TSO) and beta-naphthoflavone (BNF) have been shown to induce renal enzyme activities in rats. Thus, it was of interest to determine the effects of PBB, TSO and BNF on cephaloridine toxicity in Fischer 344 rats. Nephrotoxicity was estimated by measuring alterations in the kidney-to-body weight ratio, blood urea nitrogen and accumulation of p-aminohippurate (PAH) and tetraethylammonium by renal cortical slices. Hepatotoxicity was quantified as changes in serum glutamic pyruvic transaminase (SGPT) activity. Cephaloridine produced only minor changes in SGPT activity. Animals fed diet supplemented with 100 ppm of PBB for 10 days became less susceptible to cephaloridine nephrotoxicity. Similarly, pretreatment of animals with TSO (300 mg/kg) or BNF (100 mg/kg) for 4 days decreased cephaloridine toxicity. Thus, these results suggest that induction of renal drug-metabolizing enzyme activities by these 3 inducers may enhance some detoxification pathway(s) which convert cephaloridine to a non-toxic metabolite(s). Alternatively, treatments with these inducers may alter cephaloridine pharmacokinetics and decrease renal cortical accumulation of cephaloridine.
D000818:Animals; D001571:Benzoflavones / Q000494:pharmacology; D002509:Cephaloridine / Q000633:toxicity*; D004347:Drug Interactions; D004790:Enzyme Induction; D007668:Kidney / Q000187:drug effects / Q000201:enzymology; D010634:Phenobarbital / Q000494:pharmacology; D010882:Piperonyl Butoxide / Q000494:pharmacology; D011075:Polybrominated Biphenyls / Q000494:pharmacology; D011817:Rabbits; D051381:Rats; D011916:Rats, Inbred F344 / Q000378:metabolism*; D011919:Rats, Inbred Strains / Q000378:metabolism*; D013267:Stilbenes / Q000494:pharmacology; D019324:beta-Naphthoflavone
D001571:Benzoflavones; D011075:Polybrominated Biphenyls; D013267:Stilbenes; D019324:beta-Naphthoflavone; C025906:stilbene oxide; D002509:Cephaloridine; D010882:Piperonyl Butoxide; D010634:Phenobarbital