The disposition of monodesethylamodiaquine was studied in four healthy subjects after a single oral dose of 10 mg/kg amodiaquine base. Amodiaquine was not found in any sample, but the major metabolite monodesethylamodiaquine was detected and was assumed to be the sole derivative that contributed significantly to antimalarial activity in the blood. The best fit for the decay of the metabolite was obtained with a three-compartment model. The half-lives of the first two phases were 3.2 to 11.4 h for t1/2 alpha 1 and 22.7 to 50.3 h for t1/2 alpha 2 in plasma. The half-life of the terminal phase (t1/2 beta) was between 9 and 18.2 days. The concentration in whole blood was 4- to 6-times higher than in plasma. Three schedules (alternate days, weekly, daily) of the conventional prophylactic dose of 10 mg/kg per week were compared in six other healthy subjects. There were significant differences in the plasma monodesethylamodiaquine levels between the three schedules.

Chloroquine uptake by Plasmodium falciparum-infected human erythrocytes (RBC) was studied in vitro before and during culture by measuring the chloroquine gradient between the cells and medium (C/M) by high-pressure liquid chromatography. The C/M values were 5.9 ± 2.7 (n = 23) for uninfected RBC, 13 to 34 for six chloroquine-susceptible isolates (concentration required to inhibit 50% of parasite growth, <100 nmol/liter) in partially infected RBC (parasitemia from 0.3 to 5%) (n = 28), and 8.4 to 4.9 for four chloroquine-resistant isolates (concentration required to inhibit 50% of parasite growth, 320 to 1,500 nmol/liter) in partially infected RBC (parasitemia from 0.4 to 5%) (n = 26). Two isolates were studied before and after adaptation to continuous culture. C/M was found to decrease (34.2 to 2.1 and 19.3 to 4.9), whereas the concentration required to inhibit 50% of parasite growth increased (35 to 1,400 and 54 to 1,500 nmol/liter), thus indicating the acquisition of chloroquine resistance. These results demonstrate that chloroquine uptake decreased in RBC in which the infective strain, initially susceptible, became resistant in culture and imply that the drug is bound to ferriprotoporphyrin IX to a lesser extent or that a parasite protein competes with ferriprotoporphyrin IX to a greater extent. We suggest that genotypic modifications in the mechanism of chloroquine uptake might occur in the parasite.The rapid activity of antimalarial drugs is related to their high binding capacity to infected erythrocytes (RBC). The high accumulation of chloroquine in Plasmodium berghei-infected RBC was first demonstrated by Macomber (14). This was confirmed by Fitch (4), who showed that the accumulation was decreased when the P. berghei strains were chloroquine resistant. Later, Fitch confirmed the decrease in chloroquine uptake by Aotus trivirgatus RBC infected with chloroquine-resistant Plasmodium falciparum (5).The difference in chloroquine uptake might be due to lower penetration across infected membranes of RBC (variations in permeability), a difference in binding to the intraerythrocytic receptor ferriprotoporphyrin IX (FP), to which chloroquine is bound with high affinity (3, 8), or both.In our laboratory, we maintain long-term continuous cultures of P. falciparum strains isolated from humans. We have shown that initially chloroquine-susceptible P. falciparum isolates become resistant after adaptation to culture (13). The next step was to study chloroquine uptake by RBC infected with a P. falciparum strain when it was initially chloroquine susceptible and when it became chloroquine resistant after adaptation to culture. This was the aim of the present work. from Thailand and Tanzania) were resistant to chloroquine in vivo and in vitro (IC50, 670 and 320 nmol/liter, respectively).Isolates (uncultured specimens) were identified by a chronological number for each patient; strains (cultured for over 5 weeks) were identified by FCM (for falciparum) and a chronological number, also. Both identifications were followed by the ...

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