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.