P-glycoprotein inhibition leads to enhanced disruptive effects by anti-microtubule cytostatics at the in vitro blood-brain barrier

Purpose. To investigate whether P-glycoprotein (Pgp) protects the in vitro BBB against the cytotoxic effects of anti-tumour drugs. Methods. In an in vitro BBB coculture model the influence of the anti-micro tubule drugs vinblastine. colchicine, paclitaxel and the non-antimicrotubul e drugs doxorubicin, fluorouracil and etoposide in the absence or presence of Pgp modulators on the trans-endothelial electrical resistance (TEER), wh ich is an indicator for the integrity, was investigated. Results. In the absence of Pgp modulators vinblastine, colchicine and pacli taxel dose dependently decreased TEER values to less than 20% of control. N on-anti-microtubule drugs did not affect TEER values. Following competitive inhibition of Pgp by various Pgp modulators and substrates, even low conce ntrations of vinblastine, colchicine and paclitaxel substantially decreased TEER. IC50 values of LY 335979, SDZ-PSC 833, cyclosporin A, and verapamil were 0.03, 0.25, 0.16. and 13.7 muM, respectively. Conclusions. These results indicate that Pgp normally protects the in vitro BBB against the disruptive effects of anti-microtubule drugs. but its inte grity is lost when anti-microtubule drugs are used in combination with pote nt Pgp modulators. In addition, this procedure offers the possibility to ch aracterize Pgp modulators and substrates with respect to their efficacy and to elucidate drug interactions at the level of Pgp.