title: Enhanced oral absorption and decreased elimination of paclitaxel in mice cotreated with cyclosporin A.
abstract: 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.
authors.affiliation: Department of Clinical Chemistry, The Netherlands Cancer Institute, Amsterdam.
authors.forename: J
authors.initials: J
authors.lastname: van Asperen
authors.forename: O
authors.initials: O
authors.lastname: van Tellingen
authors.forename: M A
authors.initials: MA
authors.lastname: van der Valk
authors.forename: M
authors.initials: M
authors.lastname: Rozenhart
authors.forename: J H
authors.initials: JH
authors.lastname: Beijnen
mesh_terms: 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*
chemical_list: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000972:Antineoplastic Agents, Phytogenic; D016572:Cyclosporine; D017239:Paclitaxel