Chloroquine moa

Resistance in P falciparum can also result from decreased intravacuolar accumulation of chloroquine via a transporter encoded by the pfcrt (P falciparum chloroquine-resistance transporter) gene. After traversing the erythrocytic and plasmodial membranes, chloroquine (a diprotic weak base) is concentrated in the organism’s acidic food vacuole, primarily by ion trapping. It is in the food vacuole that the parasite digests the host cell’s hemoglobin to obtain essential amino acids. However, this process also releases large amounts of soluble heme (ferriprotoporphyrin IX), which is toxic to the parasite. To protect itself, the parasite ordinarily polymerizes the heme to hemozoin (a pigment), which is sequestered in the parasite’s food vacuole. Chloroquine specifically binds to heme, preventing its polymerization to hemozoin. The increased pH and the accumulation of heme result in oxidative damage to the membranes, leading to lysis of both the parasite and the red blood cell. The binding to heme and prevention of its polymerization appear to be a crucial step in the drug’s antiplasmodial activity, which may represent a unifying mechanism for such diverse compounds as chloroquine, quinidine, and mefloquine.