PHYSICOCHEMICAL PROPERTIES CORRELATED WITH DRUG-RESISTANCE AND THE REVERSAL OF DRUG-RESISTANCE IN PLASMODIUM-FALCIPARUM

At high molar excess, verapamil can selectively increase the accumulat ion and cytotoxicity of structurally dissimilar natural product drugs in many multidrug-resistant tumor cell lines. Such concentrations of v erapamil are also capable of increasing the accumulation and activity of chloroquine in chloroquine-resistant strains of the human malaria p arasite Plasmodium falciparum. Despite such similarities, it is not cl ear why chloroquine-resistant P. falciparum is often susceptible to cl osely related compounds such as amodiaquine, whereas cancer cells are cross-resistant to many structurally unrelated drugs. For 13 aminoquin oline and aminoacridine compounds, relative drug resistance was negati vely correlated with lipid solubility at physiological pH (r(2) = 0.90 , p < 0.0001). The ability of verapamil (5 mu M) to reverse drug resis tance was also negatively correlated with lipid solubility (r(2) = 0.8 8, p < 0.0001). Furthermore, molar refractivity was weakly correlated with relative drug resistance (r(2) = 0.46, p < 0.05) and reversal of drug resistance (r(2) = 0.52, p < 0.005). Verapamil increases chloroqu ine accumulation by resistant parasites, a mechanism suggested to acco unt for its selective chemosensitization effect. We show that the init ial rate of chloroquine accumulation by resistant parasites is increas ed by verapamil. This effect of verapamil is abolished when deoxy-gluc ose is substituted for glucose. Therefore, verapamil produces an energ y-dependent increase in the permeability of resistant parasites to chl oroquine. For a panel of four chloroquine-resistant and two chloroquin e-susceptible isolates, the effect of verapamil on the accumulation of chloroquine and monodesethyl amodiaquine was found to be correlated ( r(2) = 0.96, p < 0.001). Verapamil chemosensitization was also correla ted for the two drugs (r(2) = 0.92, p < 0.005), suggesting a common me chanism. In summary, the degree of drug resistance and the extent of v erapamil chemosensitization for a particular drug seem to be dependent on general physical features such as lipid solubility and molar refra ctivity rather than on closely defined structural parameters. These st udies provide insight into this important resistance mechanism of mala ria parasites and may provide direction for the development of new dru gs that are effective against resistant parasites.