The decrease of paclitaxel efflux by pretreatment of interferon-gamma and tumor necrosis factor-alpha after intracerebral microinjection

초록

Paclitaxel is highly efficacious in the treatment of patients suffering from a broad spectrum of neoplastic diseases. However, its efficacy against malignant glioma is very moderate. Paclitaxel is known to be a substrate for P-glycoprotein (P-gp), so this transporter may be due to insufficient access of paclitaxel to the brain. First, we investigated the brain-to-blood transport of paclitaxel across the blood-brain barrier (BBB) using the brain efflux index method. [H-3]loaclitaxel was eliminated from rat brain with an efflux transport rate of 1.87 x 10(-2) +/- 0.16 x 10(-2) min(-1). The elimination of [H-3]paclitaxel was inhibited by unlabeled paclitaxel and verapamil, suggesting a carrier-mediated transport process via P-gp. Furthermore, TNF-alpha and IFN-gamma induced significant decrease of paclitaxel efflux 1 and 24 h pretreatment. These results suggest that P-gp efflux function at the BBB is reduced by TNF-alpha and IFN-gamma. Therefore, the distribution of P-gp dependant drugs including paclitaxel in the central nervous system can be modulated by neurological diseases. (C) 2013 Elsevier B.V. All rights reserved.

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