Cyclosporine pharmacokinetics and effect in the Type I diabetic rat model

Recent clinical studies have demonstrated the potential benefit of the T-cell-specific immunosuppressant, cyclosporine, in the treatment of Type I insulin-dependent diabetes. In the present study, steady-state cyclosporine pharmacokinetics, fasting glucose and insulin levels and renal function were examined in stable insulin-dependent diabetic rats and compared to non-diabetic rats. Mean creatinine clearance 30 days following diabetes induction was not significantly different from saline controls. Cyclosporine treatment (5 mg/kg/day i.v. for 13 days) did not significantly alter creatinine clearance in either group; however, renal function of vehicle-treated diabetic rats was markedly reduced compared to other groups. Serum insulin concentrations were significantly greater in diabetic rats treated with cyclosporine compared to the control group (35.1 +/- 22.7 vs. 16.0 +/- 8.1 microU/ml; P less than 0.05). Glucose levels were proportionately reduced in diabetic rats treated with cyclosporine. Area under the concentration-time curve, half-life and volume of distribution of cyclosporine were significantly reduced in diabetic rats compared to non-diabetic controls. In summary, the pharmacokinetics and pharmacodynamics of cyclosporine were significantly different in the insulin-dependent diabetic rat model compared to normal controls. Furthermore, short-term cyclosporine therapy reduced the extent of experimental diabetic nephropathy observed in this model.