P-Glycoprotein Inhibition Leads to Enhanced Disruptive Effects by Anti-Microtubule Cytostatics at the In Vitro Blood-Brain Barrier |
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Authors: | van der Sandt Inez C J Gaillard Pieter J Voorwinden Heleen H de Boer Albertus G Breimer Douwe D |
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Institution: | (1) Leiden/Amsterdam Center for Drug Research, Division of Pharmacology, Leiden University, P.O. Box 9503, 2300 RA Leiden, The Netherlands |
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Abstract: | 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–microtubule drugs vinblastine, colchicine, paclitaxel and the non–antimicrotubule drugs doxorubicin, fluorouracil and etoposide in the absence or presence of Pgp modulators on the trans–endothelial electrical resistance (TEER), which is an indicator for the integrity, was investigated.
Results. In the absence of Pgp modulators vinblastine, colchicine and paclitaxel dose dependently decreased TEER values to less than 20% of control. Non–anti–microtubule drugs did not affect TEER values. Following competitive inhibition of Pgp by various Pgp modulators and substrates, even low concentrations 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, 0.46, and 13.7 M, respectively.
Conclusions. These results indicate that Pgp normally protects the in vitro BBB against the disruptive effects of anti–microtubule drugs, but its integrity is lost when anti–microtubule drugs are used in combination with potent Pgp modulators. In addition, this procedure offers the possibility to characterize Pgp modulators and substrates with respect to their efficacy and to elucidate drug interactions at the level of Pgp. |
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Keywords: | P– glycoprotein blood– brain barrier anti– microtubule drugs in vitro Pgp modulators |
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