CHRONOPHARMACOKINETICS OF CYCLOSPORINE-A FOLLOWING A SINGLE IV DOSE IN THE WISTAR RAT

The chronopharmacokinetics of cyclosporine A (CsA) injected at one of four circadian stages, 02, 08, 14 or 20 HALO (hours after light on), w ere studied in Wistar rats (i.v., 5 mg kg(-1)). Plasma samples were an alyzed for CsA using a specific HPLC method. The kinetic profiles were best described by a three-compartment open model. A two-way ANOVA of the data showed significant dosing time variations. The terminal half- life (22.5 +/- 2 h) was dosing time-independent. The mean half-lives o f the two distributive phases were 13 +/- 3 min and 4 +/- 1.5 h, respe ctively. Small but significant secondary peaks were noticed during the late distributive phase. There were substantial time-dependent differ ences in area under the concentration-time curve AUG: 35275 +/- 1185 v s 29087 +/- 752 mu g 1(-1) h(-1) and clearance CL: 0.142 +/- 0.005 vs 0.172 +/- 0.004 1 h(-1) kg(-1), at 08 and 20 HALO, respectively. These data indicate an apparent circadian influence on CsA pharmacokinetics after i.v. dosing, drug exposure being greater during the resting spa n.