4-AMINOQUINOLINE RESISTANCE OF PLASMODIUM-FALCIPARUM - INSIGHTS FROM THE STUDY OF AMODIAQUINE UPTAKE

The relationship between antimalarial activity and drug accumulation o f chloroquine and amodiaquine was evaluated with four chloroquine-resi stant and two chloroquine-susceptible isolates of Plasmodium falciparu m. Susceptibility of the strains to amodiaquine was correlated with su sceptibility to chloroquine (r(2) = 0.96). Similarly, accumulation of amodiaquine was correlated with accumulation of chloroquine (r(2) = 0. 94). Accumulation of both chloroquine and amodiaquine was significantl y reduced in chloroquine-resistant isolates (p < 0.005). For the panel of isolates, the accumulation ratio of both drugs was inversely propo rtional to drug susceptibility (r(2) = 0.963 and 0.994 for amodiaquine and chloroquine, respectively). Time course studies highlighted a red uced initial rate of amodiaquine accumulation in chloroquine-resistant isolates compared with chloroquine-susceptible isolates, with no evid ence of an enhanced drug efflux rate. Daunomycin, a modulator of paras ite chloroquine transport, significantly increased steady state accumu lation of both drugs in chloroquine-resistant isolates and, to a lesse r extent, in chloroquine-susceptible isolates. Furthermore, daunomycin increased the initial rate of accumulation of amodiaquine in both chl oroquine-resistant and chloroquine-susceptible isolates. Resistance to 4-aminoquinoline drugs is associated with reduced drug permeability r ather than enhanced cellular exit of preaccumulated drug, and daunomyc in seems to increase the permeability of parasites to aminoquinolines. A new model of 4-aminoquinoline resistance is proposed to take accoun t of these and earlier observations.