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 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

Effect of the ABCB1 modulators elacridar and tariquidar on the distribution of paclitaxel in nude mice

“…The in vivo experiments with NMRI nu/nu mice were performed as described by Fellner et al (2002). Six-to 8-week-old NMRI nu/nu mice were assigned to groups of three animals per time point.…”

“…However, the efficacy of paclitaxel in the systemic treatment of these tumors is variable and low. Although paclitaxel should be able to penetrate across the bloodbrain barrier because of its physiochemical properties, its access to the brain is limited because of its high affinity to the efflux transporter ABCB1 (p-glycoprotein 170, p-gp) (Fellner et al 2002;Sparreboom et al 1997;van Asperen et al 1997). By blocking the ABCB1 mediated efflux it is possible to increase the concentration of ABCB1 substrates, e.g.…”

“…The ABCB1 mediated transport is inhibited by certain substances, the so-called ABCB1 modulators (Breedveld et al 2006;Fricker and Miller 2004). In a previous study we investigated the impact of valspodar co-administration on the distribution of paclitaxel in nude mice (Fellner et al 2002). After pretreatment with valspodar (50 mg/kg, 4 h prior to the administration of 8 mg/kg paclitaxel) a six-to eightfold increase in the paclitaxel concentration in the brain compared to the paclitaxel brain levels without valspodar coapplication was measured.…”

“…In addition, the modulator is known to interact with cytochrome P450 enzymes, leading to alterations of pharmacokinetic parameters of cytostatic drug such as delayed elimination (Wandel et al 1999). Thus, the toxic side effects of chemotherapy increased, and paclitaxel doses had to be reduced, which in turn resulted in a lower amount of cytostatic drug in the brain (Fellner et al 2002).…”

Cytotoxicity and Apoptosis Enhancement in Brain Tumor Cells Upon Coadministration of Paclitaxel and Ceramide in Nanoemulsion Formulations

“…PTX has been shown to have high therapeutic activity in GBM, if the drug can be administered efficiently, such as with convection-enhanced delivery. 13,14 Recent studies showed that coadministration of the P-gp inhibitor (valspodar) was found to enhance the brain uptake of PTX, a P-gp substrate, and improve anti-tumor therapeutic effect. 15 The short chain sphingolipids, such as ceramide, which are second messengers in the cell, have been found to play a crucial role as mediators of apoptotic signaling.…”