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

Abstract

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. [3H]Paclitaxel was eliminated from rat brain with an efflux transport rate of 1.87×10−2±0.16×10−2min−1. The elimination of [3H]paclitaxel was inhibited by unlabeled paclitaxel and verapamil, suggesting a carrier-mediated transport process via P-gp. Furthermore, TNF-α and IFN-γ induced significant decrease of paclitaxel efflux 1 and 24h pre-treatment. These results suggest that P-gp efflux function at the BBB is reduced by TNF-α and IFN-γ. Therefore, the distribution of P-gp dependant drugs including paclitaxel in the central nervous system can be modulated by neurological diseases.