title: Multidrug resistance-reversing agents increase vinblastine distribution in normal tissues expressing the P-glycoprotein but do not enhance drug penetration in brain and testis.
abstract: The aim of this study was to assess whether P-glycoprotein (Pgp) inhibitors altered the blood-brain barrier and enhanced vinblastine (VBL) distribution in brain, testis and other Pgp-expressing tissues. Trifluoperazine, cyclosporin A, amiodarone, quinidine, the nifedipine analog Bay K8644 and verapamil were selected among Pgp inhibitors and were administered intraperitoneally 1 hr before an intravenous dose of 10 mg/kg VBL. Trifluoperazine and cyclosporin A were also administered intraperitoneally for 7 days before VBL. VBL and its metabolite O4-deacetylvinblastine were measured in tissues by high-performance liquid chromatography assay. None of the reversing agents (RA) appreciably raised VBL concentrations in brain and testis, whereas all except quinidine significantly enhanced VBL distribution in liver and kidney; the most effective were trifluoroperazine and cyclosporin A. In mice treated with RA and VBL combined, O4-deacetylvinblastine levels in liver and kidney reached either the same or higher levels than in mice treated with VBL alone, indicating that the increase in VBL levels is not due to inhibition of its metabolism. The main conclusions are that (1) inhibitors of Pgp, even at high doses, do not increase the permeability of the blood-brain barrier in mice, suggesting caution in the clinical use of RA combined with antitumor agents for brain tumors; and (2) several RA achieve high enough concentrations to enhance the distribution of VBL in other normal tissues expressing Pgp, thus potentially increasing VBL toxicity.
authors.affiliation: Department of Oncology, Mario Negri Institute for Pharmacological Research, Milan, Italy.
authors.forename: M
authors.initials: M
authors.lastname: Arboix
authors.forename: O G
authors.initials: OG
authors.lastname: Paz
authors.forename: T
authors.initials: T
authors.lastname: Colombo
authors.forename: M
authors.initials: M
authors.lastname: D'Incalci
mesh_terms: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000187:drug effects* / Q000378:metabolism; D000818:Animals; D001921:Brain / Q000187:drug effects*; D016572:Cyclosporine / Q000494:pharmacology; D018432:Drug Resistance, Multiple; D008297:Male; D051379:Mice; D013737:Testis / Q000187:drug effects*; D014268:Trifluoperazine / Q000494:pharmacology*; D014747:Vinblastine / Q000493:pharmacokinetics*
chemical_list: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D014268:Trifluoperazine; D014747:Vinblastine; D016572:Cyclosporine