ENHANCED ORAL ABSORPTION AND DECREASED ELIMINATION OF PACLITAXEL IN MICE COTREATED WITH CYCLOSPORINE-A

Recent experiments in mice have demonstrated that the systemic exposur e to p.o. administered paclitaxel is significantly enhanced with coadm inistration of the P-glycoprotein blocker SDZ PSC 833 (J, van Asperen et at, Br. J, Cancer, 76:1181-1183, 1997), To facilitate further resea rch on the feasibility of a clinically effective oral formulation of p aclitaxel, it is important to know whether cotreatment with a commonly applied and commercially available P-glycoprotein blocker, e.g., cycl osporin A, has a similar effect. Here, we present a detailed study abo ut the effects of cyclosporin A on the pharmacokinetics of p.o. and i. v. administered paclitaxel, Female FVB mice received a combined treatm ent of 5 or 10 mg/kg paclitaxel (either i.v. or p.o.) plus 0, 10, or 5 0 mg/kg cyclosporin A (p.o.), The plasma concentrations of paclitaxel were determined at several time points after drug administration using high-performance liquid chromatography. Calculated relative to the ar ea under the plasma concentration-time curve of i.v. administered pacl itaxel in mice treated without cyclosporin A, the oral bioavailability of paclitaxel increased from 9.3% up to 67% with coadministration of cyclosporin A. The bioavailability in mice cotreated with 10 or 50 mg/ kg cyclosporin A appeared to be similar. The effect of cyclosporin A o n the systemic exposure to p.o. administered paclitaxel was the result of both a significantly decreased clearance and an increased uptake. A histological examination revealed that the enhanced absorption was n ot caused by gastrointestinal toxicity, We conclude that cyclosporin A and SDZ PSC 833 are equally effective in increasing the systemic expo sure to p.o. administered paclitaxel, These data are promising for the development of a clinically useful oral formulation of this cytostati c drug and indicate that cyclosporin A is a suitable agent for further research of this concept.