Chloroquine Potentiates Primaquine Activity against Active and Latent Hepatic Plasmodia : Potentials and Pitfalls.

For a long while, 8-aminoquinoline compounds have been the only therapeutic agents against latent hepatic malaria parasites. These have poor activity against the blood-stage plasmodia causing acute malaria and must be used in conjunction with partner blood schizontocidal agents. We examined the impacts of one such agent, chloroquine, upon the activity of primaquine, an 8-aminoquinoline, against hepatic stages of , , , and within several systems-primary hepatocytes of , primary human hepatocytes, and stably transformed human hepatocarcinoma cell line HepG2. Primaquine exposures to formed hepatic schizonts and hypnozoites of in primary simian hepatocytes exhibited similar 50% inhibitory concentration (IC) values near 0.4 μM, whereas chloroquine in the same system exhibited no inhibitory activities. Combining chloroquine and primaquine in this system decreased the observed primaquine IC for all parasite forms in a chloroquine dose-dependent manner by an average of 18-fold. Chloroquine also decreased the primaquine IC against hepatic in primary human hepatocytes, in simian primary hepatocytes, and in primary human hepatocytes. Chloroquine had no impact on primaquine IC against in HepG2 cells and, likewise, had no impact on the IC of atovaquone (hepatic schizontocide) against in human hepatocytes. We describe important sources of variability in the potentiation of primaquine activity by chloroquine in these systems. Chloroquine potentiated primaquine activity against hepatic forms of several plasmodia. We conclude that chloroquine specifically potentiated 8-aminoquinoline activities against active and dormant hepatic-stage plasmodia in normal primary hepatocytes but not in a hepatocarcinoma cell line.