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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Introduction Paclitaxel (Taxol) and derivatives are active against various tumors (1-6) and have also been used to treat malignant glioma and brain metastases (7-9). However, brain tumors constitute a difficult problem and the therapeutic benefit of paclitaxel has been variable and low. This could be attributed to its limited entry into the CNS. Although paclitaxel is very lipophilic, concentrations in the CNS are very low after intravenous administration (10, 11). Paclitaxel appears to be a substrate of the multidrug resistance protein p-gp (12-14), and it is likely that this transporter contributes to its limited access to the brain. P-gp is expressed in high levels in cultured brain capillary endothelial cells and in intact brain capillaries (15, 16). It is localized at the luminal surface of the endothelium (17, 18), and therefore is in the correct location to restrict permeation of a variety of drugs into the CNS (19-21). Animals with reduced p-gp function show an accumulation of p-gp substrates in the brain as well as a markedly increased sensitivity to neurotoxic p-gp substrates, e.g., ivermectin (18, 22, 23). The present study identifies in vitro a mechanism that limits paclitaxel access to the CNS and outlines a strategy to circumvent it by blocking p-gp. We demonstrated that the p-gp blocker valspodar enhances paclitaxel entry into the brains of mice after intravenous dosing and that valspodar dramatically increases paclitaxel effectiveness against a human glioblastoma implanted into the CNS of nude mice. These are the first data directly demonstrating the role of p-gp in limiting the therapeutic availability of paclitaxel to the CNS. Methods Chemicals. Valspodar (SDZ PSC 833) and the fluorescent cyclosporin derivative NBDL-CS were from Novartis Pharma GmbH