Cyclosporine: action, pharmacokinetics, and effect in the BB rat model

Cyclosporine (Cy) was given to BB rats in an attempt to prevent the onset of diabetes. A dose of 15 to 20 mg/kg/d given orally or subcutaneously was associated with high Cy trough serum levels and caused nephrotoxicity and severe weight loss. Ten mg/kg/d of Cy was tolerated well. Forty rats were treated with Cy starting at 34 days of age. No Cy-treated rats developed diabetes by day 121, compared with 70% of the control rats. Once Cy was discontinued on day 121, 38% of female and 13% of male rats developed diabetes by day 169. Transient, spontaneously remitting hyperglycemia developed in nine rats. This occurred both in control rats and in rats on Cy, but it was more common in females than in males. Thus, Cy prevents diabetes mellitus in the BB rat when trough Cy serum levels greater than 100 ng/mL are achieved. Diabetes occurs in some rats after Cy is discontinued. In all treatment subgroups, diabetes occurred more frequently in females than in males.