Chloroquine Resistance in Malaria: Accessibility of Drug Receptors to Mefloquine

Abstract

The process of mefloquine accumulation was studied in mouse erythrocytes infected with either Plasmodium berghei CS (chloroquine susceptible) or P. berghei CR (chloroquine resistant). In both cases, mefloquine was accumulated by a saturable process with an apparent dissociation constant of 2.5 x 106 M and an apparent maximal capacity of 700 ,umol per kg of erythrocyte pellet; uninfected mouse erythrocytes accumulated more than half as much mefloquine as infected erythrocytes. The process of accumulation was not stimulated by providing glucose as a substrate, and it was not inhibited in infected erythrocytes by azide, iodoacetate, or incubation at 2°C. Although mefloquine was accumulated more effectively than chloroquine by uninfected erythrocytes and by erythrocytes infected with P. berghei CR, competition between chloroquine and mefloquine was observed, raising the possibility that the same process of accumulation serves both drugs. Chloroquine competitively inhibits mefloquine accumulation, with an apparent inhibitor constant of 1.7 x 10-3 M, and mefloquine competitively inhibits chloroquine accumulation, with an apparent inhibitor constant of 2 x 10' M.The same process of accumulation and the same group of receptors could serve both drugs if mefloquine has greater access than chloroquine to the receptors.Regardless of whether the same process serves both drugs, undiminished accumulation by erythrocytes infected with P. berghei CR provides an explanation for the superiority of mefloquine in treating chloroquine-resistant malaria.

Chloroquine resistance in the malarial parasite, Plasmodium falciparum

“…However, as has been pointed out in several studies, 5,75,77 this is not what is observed when comparing MQ vs. CQ accumulation experimentally; in fact, they are much more similar in magnitude, and certainly do not appear to differ by 3 orders of magnitude. 66,75,77 Figure 2 A:Predicted net fold accumulation of either CQ (circles) or MQ (squares) in DVof various pH (the X-axis) at fixed blood pH of 7.33. Note the huge differences predicted for CQ vs. MQ.…”

“…27,63,64 As early as 1967, 65 the likelihood of important CQ-heme interactions was realized, and the idea gained further momentum via the work of Fitch and colleagues. 66 Chloroquine (CQ) is one of the most successful drugs of all time because: (1) it is inexpensive, (2) it is a stable compound that travels well, (3) it can be tolerated in high doses (the therapeutic index is excellent), (4) it targets the heme digestion pathway of the intraerythrocytic malarial parasite. Additional inexpensive strategies based on Hb digestion and heme polymerization will remain an important avenue for therapy in the future.…”

The present status of malaria chemotherapy: Mefloquine, a novel antimalarial

“…Peak areas are directly compared with those of extracted standards. Recovery of mefloquine from plasma, in the range of 200-600 nglml, was between 91 and 99%; recovery of the metabolite (21a), in the range of 600-1800 nglml, was between 62 method was less than +5%. Using this method, levels of mefloquine and its metabolite were followed in the plasma of subjects up to 3 months following an oral dose of 1 g of the drug.…”

“…62 and references cited therein) using P. berghei CS(ch1oroquine susceptible)-and P. berghei CR(ch1oroquine resistant)-infected mouse erythrocytes. The pattern of mefloquine accumulation in these two systems differs markedly from that of chloroquine accumulation.…”

Investigation of the in vitro Gender-Specific Partitioning of Mefloquine in Malarial Infected Red Blood Cells and Plasma

“…Mefloquine has been reported to accumulate in P. falciparum-infected human red cells with relatively constant red cells to plasma concentration ratio of about 1-2. 26 It also has a high affinity for binding to red cell membranes 28,29 and the concentrations in red cell membranes could be 60-fold of the bathing medium and buffer saline. 30 Mefloquine is certainly one of the best antimalarial drugs for treatment and prophylaxis of malaria.…”