Influence of the hepatic drug-metabolizing enzyme-inducer phenobarbitone on cyclosporine nephrotoxicity and hepatotoxicity in renal-allografted rats.

We have investigated the influence of phenobarbitone ([PB]; 40 mg/kg/day), an inducer of hepatic drug metabolism, on high-dose cyclosporine ([CsA] 40 mg/kg/day) nephrotoxicity in normal Lewis (Lew) and renal allografted (DA X Lew F1----Lew) rats of both sexes. In untreated normal animals, CsA nephrotoxicity, assessed biochemically and histologically, in terms of acute and chronic renal structural damage, was consistently greater in male than in female rats. The capacity of PB to induce CsA metabolism was accompanied in normal rats by reductions in nephro- and hepatotoxicity and by prolonged survival of both female and male rats. Similar reductions in CsA-induced renal functional impairment and acute tubular cell injury were achieved in transplanted female (but not male) animals by concomitant PB administration. Continuous PB treatment in transplanted rats was, however, associated with the appearance of hepatic necrosis. While this effect of PB, and its failure to reduce CsA-induced chronic renal damage mitigate against its prospective value in reversing CsA toxicity, PB may nevertheless prove valuable in assessing further the role of drug metabolism in the pathogenesis of CsA nephrotoxicity.

Pathological changes developing in the rat during a 3-week course of high dosage cyclosporin A and their reversal following drug withdrawal.

Adult Sprague-Dawley rats given cyclosporin A (Cy A orally in a dose of 100 mg/kg/48 hr for 21 days displayed pronounced suppression of humoral immunity to sheep red blood cells. They showed hair loss and failure to gain weight and exhibited a progressive increase in serum urea, serum creatinine, and urinary N-acetyl-beta-D-glucosaminidase (NAG) activity, with a fall in urea clearance rate. Hypoalbuminemia and hyperbilirubinemia were observed in combination with a significant decrease in serum aspartate aminotransferase (AAT) and alkaline phosphatase levels. At 2 weeks, there was significant lymphopenia with the appearance of atypical lymphocytes in the peripheral blood. Autopsies performed on animals killed at 3 weeks revealed no light microscopic or ultrastructural differences between test and control animals, apart from some reduction in overall bone marrow cellularity in the former. During the 3-week period following withdrawal of Cy A, renal and hepatic function reverted to normal and a rebound lymphocytosis occurred. Only one of six rats autopsied 3 weeks after cessation of CY A administration showed reduced bone marrow cellularity. This study indicates that the rat may prove to be a useful experimental model for further investigation of te functional and structural changes which may be encountered in the clinical use of Cy A.