Evidence for electrogenic accumulation of mefloquine by malarial parasites

Abstract

The uptake of mefloquine and chloroquine by Plasmodium chabaudi-infected mouse erythrocytes was measured in the presence and absence of ionophores and uncoupler in order to distinguish between the pH-dependent and pH-independent absorption of these drugs. Nigericin and CCCP (carbonylcyanide m-chlorophenylhydrazone) were used to relax the proton gradients and electrical potentials across the membranes. It was found that 40-60% of the mefloquine uptake, and 90% of the chloroquine uptake, was pH-dependent, the remainder being due to passive binding to cellular constituents. The distribution ratio of the pH-dependent uptake for mefloquine was about three times greater than for chloroquine. According to the lysosomotropic weak base hypothesis in which the neutral forms of weak bases are assumed to equilibrate across membranes, the mefloquine distribution should be smaller than the chloroquine distribution: since mefloquine is singly charged and chloroquine is doubly charged, the chloroquine distribution ratio should vary as the square of the mefloquine ratio. We interpret the greater uptake ratio of mefloquine to be evidence for the involvement of secondary active transport, with drug uptake being coupled to proton outflow by an antiporter protein. It is proposed that the uptake of mefloquine is electrogenic, with the proton gradient and the electrical potential both contributing to the driving force, but that the proton gradient alone is responsible for the chloroquine uptake. © 1988.