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The chronopharmacokinetics of cyclosporine A (CsA) injected at one of four circadian stages, 02, 08, 14 or 20 HALO (hours after light on), were studied in Wistar rats (i.v., 5 mg kg−1). Plasma samples were analyzed 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 of the two distributive phases were 13 ± 3 min and 4 ± 1.5 h, respectively. Small but significant secondary peaks were noticed during the late distributive phase. There were substantial time-dependent differences in area under the concentration-time curve AUC: 35275 ± 1185 vs 29087 ± 752 μg l−1 h−1 and clearance CL: 0.142 ± 0.005 vs 0.172 ± 0.004 l 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 span. |
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