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Drug accumulation in the presence of the multidrug resistance pump: dissociation between verapamil accumulation and the action of P-glycoprotein

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We studied the interaction between the multidrug transporter, P-glycoprotein, and two compounds that interact with it: vinblastine, a classical substrate of the pump, and verapamil, a classical reverser. Steady-state levels of accumulation of these two drugs were determined in a multidrug resistant P388 leukemia cell line, P388/ADR. The time course of accumulation of these drugs, and the effect of energy starvation and the presence of chloroquine on the level of their steady-state accumulation were quite disparate. Vinblastine inhibited the accumulation of verapamil whereas it enhanced the accumulation of daunomycin, another classic substrate of P-glycoprotein. Verapamil did not compete with the intracellular binding sites of vinblastine. In all these aspects, vinblastine behaved as a typical substrate of P-glycoprotein but verapamil did not. Our data suggest that verapamil is a reverser of P-glycoprotein but that its intracellular accumulation is not affected by this membrane-bound transporter.

OriginalsprogEngelsk
TidsskriftReceptors and Channels
Vol/bind5
Udgave nummer3-4
Sider (fra-til)175-83
Antal sider9
ISSN1060-6823
StatusUdgivet - 1997

ID: 119647821