In vitro susceptibility of Plasmodium falciparum to quinine: relation to parasite density and drug distribution in culture fractions.
We have studied the importance of parasite density (2, 0.2, 0.02 and 0.002%) for the in vitro susceptibility of Plasmodium falciparum (F32 strain) to quinine. Shorter exposures (< or = 48 hours) only briefly inhibited parasites in wells with the highest initial density. Parasites reappeared after 3-5.5 days in wells with intermediate (0.2 and 0.02%) and lowest density (0.002%). Longer exposures (> or = 72 hours), however, inhibited them for much longer periods and parasites did not reappear in most of the wells with the lowest density during the 28 days of follow-up. The mean multiplication rate following reappearance was tenfold per parasite schizogony cycle. The mean elimination rate per schizogony cycle was calculated to be 99.91%. The elimination and multiplication rates were not correlated to initial parasite density. The mean ratio between quinine concentrations in erythrocytes and medium was 3.6 regardless of quinine concentrations and presence of parasites. Mean quinine-free fractions of 36 and 67% were found from total concentrations of 0.33 and 10.4 mumol/l. We conclude that initial parasite density determines the time to reappearance of parasites following quinine exposure while the elimination and multiplication rates are independent of the initial parasite density, and that quinine protein binding is concentration-dependent in vitro and lower than during treatment.
Mapaba
E
E
Unit of Tropical Pharmacology, Karolinska Institute, Huddinge, Sweden.
Ericsson
O
O
Hellgren
U
U
Rombo
L
L
D000818:Animals; D000962:Antimalarials / Q000008:administration & dosage / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D004912:Erythrocytes / Q000469:parasitology; D006801:Humans; D010963:Plasmodium falciparum / Q000187:drug effects* / Q000254:growth & development; D011156:Population Density; D011803:Quinine / Q000008:administration & dosage / Q000494:pharmacology*
D000962:Antimalarials; D011803:Quinine