AMODIAQUINE ACCUMULATION IN PLASMODIUM-FALCIPARUM AS A POSSIBLE EXPLANATION FOR ITS SUPERIOR ANTIMALARIAL ACTIVITY OVER CHLOROQUINE

Amodiaquine is a 4-aminoquinoline antimalarial whose structure is simi lar to chloroquine. In contrast to the wealth of information available about chloroquine accumulation and its relationship to activity, litt le is known about the uptake characteristics of amodiaquine, a drug th at is inherently more active against malaria parasites. In this study we have investigated the accumulation of amodiaquine in Plasmodium fal ciparum in vitro, in order to gain an insight into the mechanisms resp onsible for its superior activity over chloroquine. The driving force for parasite accumulation of the 4-aminoquinolines is proposed to be a transmembrane proton gradient maintained by a vacuolar ATPase. In the present study, amodiaquine accumulation was greatly reduced, al stead y stare, in the absence of glucose and at 0 degrees C indicating a cle ar energy dependence of uptake. Amodiaquine accumulation in Plasmodium falciparum was shown to be 2- to 3-fold greater than chloroquine accu mulation. This observation probably accounts for amodiaquine's greater inherent activity but is surprising given that amodiaquine is a weake r base than chloroquine. With this in mind we present evidence for an intraparasitic binding component in the accumulation of the 4-aminoqui nolines. Differences in binding affinity of this 'receptor' for amodia quine and chloroquine may partially explain the greater accumulation a nd in vitro potency of amodiaquine compared to chloroquine.