Antimalarial action of hydrophilic drugs: involvement of aqueous access routes to intracellular parasites.
The antimalarial action and intracellular distribution of the hydrophilic agents phloridzin (PHL) (a bioflavonoid glycoside) and desferrioxamine (DFO) (an iron chelator) were studied in cultures of Plasmodium falciparum-infected human erythrocytes. When added to cultures, these agents arrested parasite growth with IC50 values of 12 microM (PHL) and 22 microM (DFO). At 37 degrees, PHL (40 microM) was virtually impermeant to uninfected cells but permeated with a mean t1/2 of 1.5 hr in trophozoites (30% accessible cell volume) and 8 hr in rings (10% of accessible cell volume). PHL, in analogy with DFO, was demonstrably permeant to infected cells harboring mature forms of the parasites. Permeation was restricted to only a fraction of the infected cell volume. PHL elicited inhibition of nucleic acid synthesis within 1 hr of exposure of trophozoites to PHL (40 microM) and in > 8 hr of exposure of rings. Red cell containers into which millimolar concentrations of PHL or DFO were encapsulated demonstrably supported parasite invasion and subsequent parasite growth and maturation (48-hr incubation). Under culture conditions, uninfected or parasite-infected red cell containers that were loaded with either agent retained the drugs for at least 42 hr at hundred-micromolar concentrations. The agent present in the cells was fully active after release from cells and administration to test cultures of parasites. PHL added to parasite cultures was active at micromolar concentrations, but when present intracellularly it was virtually inactive even at millimolar concentrations. The data presented are consistent with direct access of hydrophilic agents from medium to parasite, a process referred to as fenestration. Permeation into parasites might constitute the rate-limiting step in drug uptake and drug-mediated arrest of parasite growth by PHL and DFO. The putative role of the parasitophorous duct in providing aqueous access routes from medium to parasites is discussed.
Loyevsky
M
M
Department of Biological Chemistry, Hebrew University of Jerusalem, Israel 91904.
Cabantchik
Z I
ZI
D000818:Animals; D000962:Antimalarials / Q000493:pharmacokinetics* / Q000494:pharmacology; D002478:Cells, Cultured; D003676:Deferoxamine / Q000493:pharmacokinetics; D004912:Erythrocytes / Q000378:metabolism / Q000469:parasitology*; D006801:Humans; D010695:Phlorhizin / Q000493:pharmacokinetics* / Q000494:pharmacology; D010963:Plasmodium falciparum / Q000187:drug effects / Q000254:growth & development / Q000378:metabolism*; D014867:Water
D000962:Antimalarials; D014867:Water; D010695:Phlorhizin; D003676:Deferoxamine