Modulation of the function of human MDR1 P-glycoprotein by the antimalarial drug mefloquine

MDR1 P-glycoprotein in membranes of human tumor cells of the CEM/VBL(100) line was selectively labelled using photoreactive analogs of verapamil, N-(p-azido-3-[I-125]salicyl)amino-verapamil ([I-125]ASA-V) and prazosin, 2-[4-(4-azido-3-[I-125]iodobenzoyl)piperazin-1-yl]4-amino-6,7-dimethoxyyquinazoline ([I-125]ASA-P). Mefloquine, a quinolinemethanol antimalarial drug, was shown to inhibit the labelling of P-glycoprotein with an efficiency similar to that for verapamil, a known chemosensitizer. By contrast, chloroquine competed poorly for the binding site on P-glycoprotein. Mefloquine also inhibited the functional activity of P-glycoprotein. It decreased the rates of extrusion of [H-3]vinblastine and the fluorescent dyes, fluo-3 acetomethoxy ester and rhodamine 123, from drug-resistant cells and decreased the level of resistance of these cells to vinblastine. The ability of mefloquine to inhibit P-glycoprotein function may be involved in the neurotoxic side-effects occasionally associated with the use of mefloquine as an antimalarial drug. Copyright (C) 1996 Elsevier Science Inc.