Transport of paclitaxel (Taxol) across the blood-brain barrier in vitro and in vivo.
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.
Fellner
Stephan
S
Institute of Pharmacy, University of Regensburg, Regensburg, Germany.
Bauer
Björn
B
Miller
David S
DS
Schaffrik
Martina
M
Fankhänel
Martina
M
Spruss
Thilo
T
Bernhardt
Günther
G
Graeff
Claudia
C
Färber
Lothar
L
Gschaidmeier
Harald
H
Buschauer
Armin
A
Fricker
Gert
G
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
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000972:Antineoplastic Agents, Phytogenic; D003524:Cyclosporins; D017239:Paclitaxel; C070272:valspodar