title: Transport of paclitaxel (Taxol) across the blood-brain barrier in vitro and in vivo.
abstract: Paclitaxel concentrations in the brain are very low after intravenous injection. Since paclitaxel is excluded from some tumors by p-glycoprotein (p-gp), the same mechanism may prevent entry into the brain. In vitro, paclitaxel transport was examined in capillaries from rat brains by confocal microscopy using BODIPY Fl-paclitaxel. Western blots and immunostaining demonstrated apical expression of p-gp in isolated endothelial cells, vessels, and tissue. Secretion of BODIPY Fl-paclitaxel into capillary lumens was specific and energy-dependent. Steady state luminal fluorescence significantly exceeded cellular fluorescence and was reduced by NaCN, paclitaxel, and SDZ PSC-833 (valspodar), a p-gp blocker. Leukotriene C(4) (LTC(4)), an Mrp2-substrate, had no effect. Luminal accumulation of NBDL-cyclosporin, a p-gp substrate, was inhibited by paclitaxel. In vivo, paclitaxel levels in the brain, liver, kidney, and plasma of nude mice were determined after intravenous injection. Co-administration of valspodar led to increased paclitaxel levels in brains compared to monotherapy. Therapeutic relevance was proven for nude mice with implanted intracerebral human U-118 MG glioblastoma. Whereas paclitaxel did not affect tumor volume, co-administration of paclitaxel (intravenous) and PSC833 (peroral) reduced tumor volume by 90%. Thus, p-gp is an important obstacle preventing paclitaxel entry into the brain, and inhibition of this transporter allows the drug to reach sensitive tumors within the CNS.
authors.affiliation: Institute of Pharmacy, University of Regensburg, Regensburg, Germany.
authors.forename: Stephan
authors.initials: S
authors.lastname: Fellner
authors.forename: Björn
authors.initials: B
authors.lastname: Bauer
authors.forename: David S
authors.initials: DS
authors.lastname: Miller
authors.forename: Martina
authors.initials: M
authors.lastname: Schaffrik
authors.forename: Martina
authors.initials: M
authors.lastname: Fankhänel
authors.forename: Thilo
authors.initials: T
authors.lastname: Spruss
authors.forename: Günther
authors.initials: G
authors.lastname: Bernhardt
authors.forename: Claudia
authors.initials: C
authors.lastname: Graeff
authors.forename: Lothar
authors.initials: L
authors.lastname: Färber
authors.forename: Harald
authors.initials: H
authors.lastname: Gschaidmeier
authors.forename: Armin
authors.initials: A
authors.lastname: Buschauer
authors.forename: Gert
authors.initials: G
authors.lastname: Fricker
mesh_terms: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000502:physiology; D000818:Animals; D000972:Antineoplastic Agents, Phytogenic / Q000493:pharmacokinetics*; D001692:Biological Transport; D001812:Blood-Brain Barrier; D001932:Brain Neoplasms / Q000188:drug therapy; D002196:Capillaries / Q000378:metabolism; D002478:Cells, Cultured; D003524:Cyclosporins / Q000494:pharmacology; D005909:Glioblastoma / Q000378:metabolism; D005910:Glioma / Q000188:drug therapy; D006801:Humans; D017239:Paclitaxel / Q000493:pharmacokinetics* / Q000627:therapeutic use; D013552:Swine; D014407:Tumor Cells, Cultured
chemical_list: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000972:Antineoplastic Agents, Phytogenic; D003524:Cyclosporins; D017239:Paclitaxel; C070272:valspodar