Simulation of kinetic data on the influx and efflux of chloroquine by erythrocytes infected with Plasmodium falciparum. Evidence for a drug-importer in chloroquine-sensitive strains.

Literature data on influx and efflux kinetics of chloroquine (CQ) with erythrocytes infected with the malaria parasite Plasmodium falciparum were simulated using a four-compartment model with first-order exchange between the compartments. The four compartments represent (1) the buffer surrounding the infected erythrocyte; (2) the cytosol of the host erythrocyte; (3) the parasite cytosol; and (4) the food vacuole. Simulations showed that basal membrane transport of CQ, estimated from data on influx of CQ into uninfected red cells, largely accounts for uptake and release of CQ by erythrocytes infected with two different CQ-resistant (CQ-R) parasite strains. In contrast, the rate of uptake of CQ by erythrocytes infected with a CQ-sensitive (CQ-S) strain is substantially higher than predicted by uptake with membrane transfer by basal diffusion of CQ. Simulations also indicate that the difference in kinetics of CQ uptake by erythrocytes infected with the CQ-S and CQ-R strains can be explained by a net increase in the inward permeability coefficient at the host erythrocyte membrane, the composite membrane surrounding the parasite or the food vacuole membrane. The results are consistent with the presence of a drug-importer for CQ in erythrocytes infected with sensitive strains, which is absent in those infected with resistant strains. They are not consistent with the hypothesis that CQ resistance is attributable to a drug-exporter in resistant cells which is lacking in sensitive cells.