Mutually co-operative interactions between modulators of P-glycoprotein.

We measured the effects of combinations of verapamil, vinblastine, mefloquine, and tamoxifen, all being modulators of the multidrug resistance pump, P-glycoprotein, on the accumulation of labelled daunomycin into multidrug-resistant P388 leukemia cells at 37 degrees C. We found that, contrary to our initial expectations (based on Ayesh, Shao and Stein (1996) Biochim. Biophys. Acta 1316, 8), vinblastine, mefloquine, and tamoxifen all appeared to interact with one another synergistically, i.e. by the kinetics of a non-competitive interaction. A simple kinetic analysis showed that pairs of co-operating modulators can give apparent non-competitive behaviour, but refined kinetic analysis enables the two types of interaction to be distinguished. The modulators vinblastine, mefloquine, and tamoxifen thus appear to co-operate with one another in pairs to bring about reversal of P-glycoprotein. This may have important implications for the design of new modulators of P-glycoprotein.