P-glycoprotein inhibition leads to enhanced disruptive effects by anti-microtubule cytostatics at the in vitro blood-brain barrier.
OBJECTIVE
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-anti-microtubule 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 microM, 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.
van der Sandt
I C
IC
Leiden/Amsterdam Center for Drug Research, Division of Pharmacology, Leiden University, The Netherlands. I.sandt@lacdr.leidenuniv.nl
Gaillard
P J
PJ
Voorwinden
H H
HH
de Boer
A G
AG
Breimer
D D
DD
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000037:antagonists & inhibitors*; D000465:Algorithms; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D001253:Astrocytes / Q000187:drug effects / Q000378:metabolism; D001812:Blood-Brain Barrier / Q000187:drug effects / Q000502:physiology*; D002417:Cattle; D002463:Cell Membrane Permeability / Q000187:drug effects; D017097:Electric Impedance; D004730:Endothelium, Vascular / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D008870:Microtubules / Q000187:drug effects*; D008954:Models, Biological
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000970:Antineoplastic Agents