Differences intrans‐stimulated chloroquine efflux kinetics are linked to PfCRT inPlasmodium falciparum

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Abstract
Summary: The mechanism underpinning chloroquine drug resistance in the human malarial parasitePlasmodium falciparumhas remained controversial. Currently discussed models include a carrier or a channel for chloroquine, the former actively expelling the drug, the latter facilitating its passive diffusion, out of the parasite's food vacuole, where chloroquine accumulates and inhibits haem detoxification. Here we have challenged both models using an establishedtrans‐stimulation efflux protocol. While carriers may demonstratetrans‐stimulation, channels do not. Our data reveal that extracellular chloroquine stimulates chloroquine efflux in the presence and absence of metabolic energy in both chloroquine‐sensitive and ‐resistant parasites, resulting in a hyperbolic increase in the apparent initial efflux rates as the concentration of external chloroquine increases. In the absence of metabolic energy, the apparent initial efflux rates were comparable in both parasites. Significant differences were only observed in the presence of metabolic energy, where consistently higher apparent initial efflux rates were found in chloroquine‐resistant parasites. Astrans‐stimulation is characteristic of a carrier, and not a channel, we interpret our data in favour of a carrier for chloroquine being present in both chloroquine‐sensitive and ‐resistant parasites, however, with different transport modalities.