Evidence for a possible dose-dependent pharmacokinetics of Cyclosporin-A in the rat.

Cyclosporin-A (Cy-A) was administered to rats intravenously (i.v.) at different dosages (20, 40 and 80 mg/kg body weight). At the lower dose (20 mg/kg), the blood levels decreased biphasically and could be described by an open linear two-compartment model with excretion from the central compartment only. The t 1/2 values for the alpha-distribution and beta-elimination phases were about 6 min and 16.5 h, respectively. At higher dose levels (40 and 80 mg/kg), the involvement of an additional compartment became apparent. The blood concentration/time data sets obtained with 40 and 80 mg/kg doses were best described by an open linear three-compartment model. The 24-h urine and bile excretions were in the order of 10 and 20% of the total administered dose. The values for the normalized areas under the plasma concentration/time curves obtained at different Cy-A doses (20, 40 and 80 mg/kg) were about 1, 3 and 25, respectively.