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Amodiaquine accumulation in Plasmodium falciparum as a possible explanation for its superior antimalarial activity over chloroquine.
- Source :
-
Molecular and biochemical parasitology [Mol Biochem Parasitol] 1996 Sep; Vol. 80 (1), pp. 15-25. - Publication Year :
- 1996
-
Abstract
- Amodiaquine is a 4-aminoquinoline antimalarial whose structure is similar to chloroquine. In contrast to the wealth of information available about chloroquine accumulation and its relationship to activity, little is known about the uptake characteristics of amodiaquine, a drug that is inherently more active against malaria parasites. In this study we have investigated the accumulation of amodiaquine in Plasmodium falciparum in vitro, in order to gain an insight into the mechanisms responsible 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, at steady state, in the absence of glucose and at 0 degrees C indicating a clear energy dependence of uptake. Amodiaquine accumulation in Plasmodium falciparum was shown to be 2- to 3-fold greater than chloroquine accumulation. This observation probably accounts for amodiaquine's greater inherent activity but is surprising given that amodiaquine is a weaker base than chloroquine. With this in mind we present evidence for an intraparasitic binding component in the accumulation of the 4-aminoquinolines. Differences in binding affinity of this 'receptor' for amodiaquine and chloroquine may partially explain the greater accumulation and in vitro potency of amodiaquine compared to chloroquine.
- Subjects :
- Adenosine Triphosphate metabolism
Ammonium Chloride pharmacology
Amodiaquine pharmacology
Animals
Anti-Bacterial Agents pharmacology
Antimalarials pharmacology
Biological Transport, Active
Chloroquine metabolism
Chloroquine pharmacology
Enzyme Inhibitors pharmacology
Glucose metabolism
Hydrogen-Ion Concentration
Ionophores pharmacology
Kinetics
Nigericin pharmacology
Plasmodium falciparum drug effects
Proton-Translocating ATPases antagonists & inhibitors
Protons
Amodiaquine metabolism
Antimalarials metabolism
Macrolides
Plasmodium falciparum metabolism
Subjects
Details
- Language :
- English
- ISSN :
- 0166-6851
- Volume :
- 80
- Issue :
- 1
- Database :
- MEDLINE
- Journal :
- Molecular and biochemical parasitology
- Publication Type :
- Academic Journal
- Accession number :
- 8885219
- Full Text :
- https://doi.org/10.1016/0166-6851(96)02655-2