Chloroquine Potentiates Primaquine Activity Against Active and Latent Hepatic Plasmodia Ex vivo: Potentials and Pitfalls.
Dembélé L., Franetich J-F., Soulard V., Amanzougaghene N., Tajeri S., Bousema T., van Gemert G-J., Le Grand R., Dereuddre-Bosquet N., Baird JK., Mazier D., Snounou G.
8-aminoquinoline compounds have long 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 Plasmodium cynomolgi, Plasmodium yoelii, Plasmodium berghei, and Plasmodium falciparum within several ex vivo systems: primary hepatocytes of Macaca fascicularis; primary human hepatocytes; and stably transformed human hepatocarcinoma cell line HepG2. Primaquine exposures to formed hepatic schizonts and hypnozoites of P. cynomolgi in primary simian hepatocytes exhibited similar IC50 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 IC50 for all parasite forms in a chloroquine dose-dependent manner by an average of 18-fold. Chloroquine also decreased the primaquine IC50 against hepatic P. falciparum in primary human hepatocytes, P. berghei in simian primary hepatocytes, and P. yoelii in primary human hepatocytes. Chloroquine had no impact on primaquine IC50 against P. yoelii in HepG2 cells, and likewise had no impact on the IC50 of atovaquone (hepatic schizontocide) against P. falciparum 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.