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: Stephan Fellner, Björn Bauer, David S Miller, Martina Schaffrik, Martina Fankhänel, Thilo Spruss, Günther Bernhardt, Claudia Graeff, Lothar Färber, Harald Gschaidmeier, Armin Buschauer, Gert Fricker
• Journal: The Journal of clinical investigation (J Clin Invest) Vol. 110 Issue 9 Pg. 1309-18 (Nov 2002) ISSN: 0021-9738 [Print] United States
• PMID: 12417570 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• ATP Binding Cassette Transporter, Subfamily B, Member 1
• Antineoplastic Agents, Phytogenic
• Cyclosporins
• Paclitaxel
• valspodar

Topics

• ATP Binding Cassette Transporter, Subfamily B, Member 1 (physiology)
• Animals
• Antineoplastic Agents, Phytogenic (pharmacokinetics)
• Biological Transport
• Blood-Brain Barrier
• Brain Neoplasms (drug therapy)
• Capillaries (metabolism)
• Cells, Cultured
• Cyclosporins (pharmacology)
• Glioblastoma (metabolism)
• Glioma (drug therapy)
• Humans
• Paclitaxel (pharmacokinetics, therapeutic use)
• Swine
• Tumor Cells, Cultured