Studies on the antimalarial mode of action of quinoline-containing drugs: time-dependence and irreversibility of drug action, and interactions with compounds that alter the function of the parasite's food vacuole.
The quinoline-containing antimalarial drugs chloroquine, quinine and mefloquine exert an irreversible inhibitory effect on erythrocytic stages of Plasmodium falciparum grown in culture. Inhibition is time- and concentration-dependent and the full effect is observed after 2-6 hours of exposure to the drug. Washing of infected cells after drug exposure in the presence of NH4Cl to accelerate drug efflux, intensifies the inhibitory effect of chloroquine, probably due to the pH-dependent release of highly concentrated drug from the acidic food vacuole of the parasite. When both antimalarials and NH4Cl are present in the culture, drug effect is reduced, as expected from the demonstrable alkalinization of the food vacuole and the consequent reduction in drug accumulation. The protease inhibitor leupeptin inhibits digestion of ingested host cell cytosol, and thus inhibits parasite growth, though reversibly so (Rosenthal et al, J. Clin. Invest. 82 1560-1566 (1988)). Thus, although the antimalarials also inhibit the feeding process, this is not the cause of their irreversible action. Leupeptin is found to be antagonistic to antimalarials' action, suggesting that the drugs form complexes with products of host cell digestion that are responsible for irreversible inhibition of parasite growth.
Department of Biological Chemistry, Hebrew University of Jerusalem, Israel.
M
M
Krugliak
H
H
Ginsburg
D000643:Ammonium Chloride / Q000494:pharmacology*; D000818:Animals; D000962:Antimalarials / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D004338:Drug Combinations; D004347:Drug Interactions; D006863:Hydrogen-Ion Concentration; D007976:Leupeptins / Q000494:pharmacology*; D010963:Plasmodium falciparum / Q000187:drug effects*; D011804:Quinolines / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D013997:Time Factors
D000962:Antimalarials; D004338:Drug Combinations; D007976:Leupeptins; D011804:Quinolines; D000643:Ammonium Chloride; C032854:leupeptin