They showed that even high doses of these inhibitors did not substantially increase the accumulation of vinblastine into the brain. (12) examined the influence of the Pgp inhibitors trifluoperazine, cyclosporin A, amiodaron, quinidine, Bay K8644, and verapamil on the brain penetration of vinblastine. The pivotal role of Pgp in this matter does suggest that inhibition of this drug transporter may be an attractive mode to increase intracerebral penetration of cytotoxic agents and consequently to increase the efficacy of chemotherapy against CNS tumors. These results suggest that the lack of efficacy of chemotherapy in the treatment of brain tumors may be, at least in part, a pharmacokinetic problem. In those mice, the penetration of vinblastine in the brain was 7–46-fold higher than that in the wild-type controls (11), showing that Pgp restricts the entry of its substrates into the brain. The generation of mice with disrupted Pgp genes (Pgp knockout mice) confirmed the important protective pharmacological function of Pgp in the BBB (9, 10). Subsequent studies have revealed that Pgp is also present in many normal tissues, including the liver, kidney, intestines, and brain (8). Initially, Pgp was discovered by its ability to confer multidrug resistance in mammalian tumor cells by active extrusion of a wide range of cytotoxic drugs (7). The presence of the multidrug transporter Pgp at the luminal side of the endothelial cells of the blood capillaries in the brain provides an explanation for these observations (4, 5, 6). However, there are many examples of relatively hydrophobic substances, including a broad range of potent anticancer drugs ( e.g., Vinca alkaloids, taxanes, anthracyclines, and epipodophyllotoxins), that are unable to gain access to the brain. Strong hydrophobicity, as defined by a high octanol-water partition coefficient, is an essential characteristic of a substance to cross the BBB (2, 3). As a consequence, substances can enter the brain only by passive transcellular diffusion or by selective carrier transport through the endothelial cells. In contrast to endothelial cells in most other organs, brain endothelial cells possess several barrier properties including close linkage by tight junctions, absence of fenestrations, and low pinocytic activity (1). Effective drug accumulation into the brain is prevented by the BBB, 3 which is physically located in the brain endothelial cells. It is warranted to test paclitaxel in combination with GF120918 in experimental brain tumor models and in clinical trials.Īlthough the brain is among the best perfused organs in the body, most drugs do not accumulate into this tissue to levels that are therapeutically relevant. After further optimization of the dose and schedule of GF120918, we could achieve paclitaxel brain levels of about 80–90% of those reached in Pgp knockout mice. Obviously, cyclosporin A and PSC833 markedly inhibited several elimination pathways of paclitaxel, whereas the reduced clearance of paclitaxel by GF120918 was most probably related to the inhibition of Pgp alone. Both cyclosporin A and PSC833 also markedly increased the plasma levels of paclitaxel in contrast to GF120918. Increased brain uptake was observed with cyclosporin A (3-fold), PSC833 (6.5-fold), and GF120918 (5-fold), although the levels were lower than that observed in Pgp knockout mice (11-fold increase). Pgp knockout mice were used as reference for complete blockade of Pgp and to determine the selectivity of Pgp inhibitors on the pharmacokinetics of paclitaxel. Plasma and tissues were collected at 1, 4, 8, and 24 h and analyzed for paclitaxel by high-performance liquid chromatography. We have determined the efficacy of several (putative) inhibitors of Pgp (cyclosporin A, PSC833, GF120918, and Cremophor EL) on the penetration of paclitaxel into the mouse brain. P-Glycoprotein (Pgp) in the blood-brain barrier limits the uptake of substrate drugs into the brain.
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