RELATIONSHIP OF GLOBAL CHLOROQUINE TRANSPORT AND REVERSAL OF RESISTANCE IN PLASMODIUM-FALCIPARUM

Control of falciparum malaria has become almost impossible in many are as due to the development of resistance to chloroquine and other antim alarial drugs. Verapamil and a number of unrelated compounds which che mosensitise multi-drug resistant cancer cells also enhance chloroquine susceptibility in Plasmodium falciparum Chloroquine is accumulated to lower levels in resistant plasmodia, hence the reversal of chloroquin e resistance has been attributed to the ability of chemosensitising ag ents to increase the amount of chloroquine accumulated by the resistan t parasite. We have conducted a detailed examination of the effect of verapamil on chloroquine sensitivity and its relationship to chloroqui ne accumulation. The ability of verapamil to increase steady-state chl oroquine accumulation was found to be totally insufficient to explain the increase in chloroquine sensitivity caused by the drug. In contras t, when chloroquine accumulation was increased by raising the pH gradi ent, the corresponding shifts in sensitivity to chloroquine could be a ccurately predicted. These results were confirmed with other classes o f chemosensitisers and we conclude that an alternative mechanistic exp lanation is required to completely explain the reversal of chloroquine resistance in P. falciparum.