Effect of phenobarbital and cimetidine on experimental cyclosporine nephrotoxicity: Preliminary observations

Cyclosporine is metabolized by the hepatic microsomal cytochrome P-450 mixed function oxidases. To determine the effects of inducers and inhibitors of this enzyme on nephrotoxicity, male Fischer 344 rats were treated with cyclosporine in doses of 25 mg/kg and 40 mg/kg by daily gavage for 14 days. Groups of animals were given phenobarbital 75 mg/kg i.p., cimetidine 75 mg/kg i.p., or .9% saline i.p. for 3 days prior to starting cyclosporine and throughout therapy. Animals treated with the oil vehicle for cyclosporine served as controls. Animals receiving cyclosporine together with phenobarbital had better preservation of glomerular filtration rate than did other cyclosporine-treated animals. Cimetidine did not enhance cyclosporine nephrotoxicity. Direct tubular toxicity was not evident using cortical slice transport of tetraethylammonium, fractional excretion of sodium and light microscopy as markers. If phenobarbital protects from cyclosporine nephrotoxicity because of its enzyme inducing action, it would follow that the parent drug and not a toxic metabolite mediated renal dysfunction. Based on the decreased glomerular filtration rate in the absence of overt tubular damage the major mechanism of cyclosporine nephrotoxicity is probably related to vascular or glomerular effects of the drug.