Enhanced oral absorption and decreased elimination of paclitaxel in mice cotreated with cyclosporin A.
Recent experiments in mice have demonstrated that the systemic exposure to p.o. administered paclitaxel is significantly enhanced with coadministration of the P-glycoprotein blocker SDZ PSC 833 (J. van Asperen et al, Br. J. Cancer, 76: 1181-1183, 1997). To facilitate further research on the feasibility of a clinically effective oral formulation of paclitaxel, it is important to know whether cotreatment with a commonly applied and commercially available P-glycoprotein blocker, e.g., cyclosporin A, has a similar effect. Here, we present a detailed study about the effects of cyclosporin A on the pharmacokinetics of p.o. and i.v. administered paclitaxel. Female FVB mice received a combined treatment of 5 or 10 mg/kg paclitaxel (either i.v. or p.o.) plus 0, 10, or 50 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 area under the plasma concentration-time curve of i.v. administered paclitaxel 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 on 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 not caused by gastrointestinal toxicity. We conclude that cyclosporin A and SDZ PSC 833 are equally effective in increasing the systemic exposure to p.o. administered paclitaxel. These data are promising for the development of a clinically useful oral formulation of this cytostatic drug and indicate that cyclosporin A is a suitable agent for further research of this concept.
van Asperen
J
J
Department of Clinical Chemistry, The Netherlands Cancer Institute, Amsterdam.
van Tellingen
O
O
van der Valk
M A
MA
Rozenhart
M
M
Beijnen
J H
JH
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000502:physiology*; D000042:Absorption; D000284:Administration, Oral; D000818:Animals; D000972:Antineoplastic Agents, Phytogenic / Q000493:pharmacokinetics*; D001682:Biological Availability; D016572:Cyclosporine / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D005260:Female; D051379:Mice; D017239:Paclitaxel / Q000493:pharmacokinetics*
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000972:Antineoplastic Agents, Phytogenic; D016572:Cyclosporine; D017239:Paclitaxel