KINETIC MODELING OF CHLOROQUINE UPTAKE BY MALARIA-INFECTED ERYTHROCYTES - ASSESSMENT OF THE FACTORS THAT MAY DETERMINE DRUG-RESISTANCE

The antimalarial chloroquine, by virtue of its weak base properties, concentrates in the acidic compartment(s) of the intraerythrocytic parasite. Drug accumulation is essential for it to exert its pharmacological activity. Drug resistance has been thought to result from insufficient acidification of drug-accumulating organelle(s), (due to weakened proton pump activity and/or proton leak) or to result from the action of the recently suggested active efflux drug pump. In this work we have devised a kinetic model which takes into account the various processes that have been postulated to account for acidification and drug fluxes. Using this model to analyse the time-course of chloroquine uptake and the steady-state levels of drug accumulation, in strains of Plasmodium falciparum which display variable drug resistance, we demonstrate that drug resistance is compatible with the existence of a weakened proton pump in the resistant parasite strains. Consistent with recent molecular studies that show no correlation between the presence of the multidrug efflux pump gene and the phenotypic expression of chloroquine resistance, our analysis fails to detect any such pump activity. We also show that analysis of drug efflux kinetics cannot distinguish between the possible modes of drug resistance.