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 microsc...
Gespeichert in:
| Hauptverfasser: | , , , |
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| Dokumenttyp: | Article (Journal) |
| Sprache: | Englisch |
| Veröffentlicht: |
2002
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| In: |
The journal of clinical investigation
Year: 2002, Jahrgang: 110, Heft: 9, Pages: 1309-1318 |
| ISSN: | 1558-8238 |
| DOI: | 10.1172/JCI15451 |
| Online-Zugang: | Verlag, kostenfrei, Volltext: http://dx.doi.org/10.1172/JCI15451
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| Verfasserangaben: | Stephan Fellner, Björn Bauer, David S. Miller, Martina Schaffrik, Martina Fankhänel, Thilo Spruß, Günther Bernhardt, Claudia Graeff, Lothar Färber, Harald Gschaidmeier, Armin Buschauer, and Gert Fricker |
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| 245 | 1 | 0 | |a Transport of paclitaxel (Taxol) across the blood-brain barrier in vitro and in vivo |c Stephan Fellner, Björn Bauer, David S. Miller, Martina Schaffrik, Martina Fankhänel, Thilo Spruß, Günther Bernhardt, Claudia Graeff, Lothar Färber, Harald Gschaidmeier, Armin Buschauer, and Gert Fricker |
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| 520 | |a 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 C4 (LTC4), 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. | ||
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