Plasma protein binding of quinine was measured in 12 patients with cerebral malaria on the first and seventh day of treatment, and in 7 patients with uncomplicated falciparum malaria on admission and also one month later. Binding was significantly higher and therefore the proportion of free drug was lower in cerebral malaria patients (free: total quinine concentration; 7.2 +/- 3.5%, mean +/- SD, on admission; 7.4 +/- 5.3% on day 7) compared with uncomplicated malaria patients on admission (10.2 +/- 5.8%) or following recovery (11.0 +/- 5.5%, n = 6) P = 0.011. Binding was significantly correlated with the red cell/total concentration ratio r = 0.56, P less than 0.0001. The ratio of cerebrospinal fluid to free (unbound) plasma quinine was 0.55 +/- 0.33 which suggests that quinine does not freely cross the blood brain barrier. These findings are relevant to the interpretation of total plasma or serum concentration, and may explain the rarity of serious quinine toxicity in severe falciparum malaria.

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1 Chloroquine diphosphate (3 mg base kg-1) was given by constant rate intravenous injection over 10 min to 12 healthy adult male volunteers. Plasma concentrations of chloroquine and the principal metabolite desethylchloroquine, electrocardiograph intervals, and arterial blood pressure were measured at frequent intervals to determine the relationship between cardiovascular effects and plasma concentrations.2 Peak plasma concentrations ranged between 784 and 6649 (mean 2913) ng ml-'. The decline in plasma concentrations was multiexponential with an initial rapid distribution phase; mean (+ s.d.) first order rate constant 0.65 + 0.14 min7t, and an estimated apparent volume of the central compartment of 0.18 + 0.15 1 kg-1. 3 There was no serious toxicity, but subjective side effects were reported in all patients and there was a significant fall in systolic blood pressure (110 + 9.5 to 101 ± 12.5 mm Hg; P = 0.03) and rise in heart rate which paralleled the change in plasma chloroquine concentrations. 4 Coincident with changes in blood pressure, there was a significant prolongation of the electrocardiograph QRS interval; 81 + 15 to 92 + 13 ms (P < 0.01) but no change in the QTc interval. 5 These findings suggest that the cardiovascular toxicity of parenteral chloroquine is related to transiently high plasma concentrations occurring early in the distribution phase. This results from incomplete distribution from a central compartment that is approximately one thousand times smaller than the eventual total apparent volume of distribution at steady state. Rate of administration is therefore a major determinant of toxicity.

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1 Quinine dihydrochloride (10 mg or, in two patients, a loading dose of 20 mg kg-) was infused intravenously over 4 h in ten severely ill but conscious women with falciparum malaria complicating the third trimester of pregnancy. 2 Plasma quinine concentrations, measured spectrophotofluorimetrically after benzene extraction, fitted closely a single exponential decline after the intravenous infusion. These data were therefore fitted to a one compartment model: total apparent volume of distribution, V, 0.96 + 0.271 kg-' (+ s.d.), elimination half-time (t112,z), 11.3 ± 4.3 h, total clearance, 1.22 + 0.77 ml min7l kg-. There was no relationship between arterial blood pressure and plasma quinine concentrations. 3 Eight women delivered of live infants while taking quinine, had placental cord plasma quinine concentrations from 1.0 to 4.6 mg 1-1 (mean 2.4) which correlated significantly with maternal plasma quinine concentrations (r = 0.78, t = 3.06, P < 0.05). The mean (+ s.d.) ratio of cord plasma to maternal plasma quinine concentration was 0.32 + 0.14.Heart blood from a foetus aborted at term had a plasma quinine concentration of 2.8 mg 171; simultaneous maternal plasma quinine was 7.1 mg 1-1 (ratio 0.39). 4 Breast milk quinine concentrations and milk to plasma ratios were 0.5-3.6 mg 1-1 (mean 2.6) and 0.11-0.53 (mean 0.31) in twenty-five women who were breast-feeding and had taken oral quinine sulphate for 1-10 days (mean 4.0). Five women with more serious infections received intravenous quinine; breast milk quinine concentrations ranged between 0.5 and 8.0 mg 171 (mean 3.4). Corresponding milk to plasma ratios were 0.11 to 0.32 (mean 0.21).

1 Chloroquine diphosphate (15 mg base kg-") was given by constant rate intravenous infusion to two groups of Thai subjects. Eleven were patients with malaria (10 with Plasmodium vivax and one case with Plasmodium malariae) and 10 were healthy normal volunteers. 2 Plasma and packed red-cell concentrations of chloroquine, electrocardiographic intervals, arterial blood pressure and pulse were measured at frequent intervals.3 Peak plasma concentrations at the end of the infusion ranged from 979 to 2,900 ng ml-' in the malaria patients. In the group of healthy subjects the range was 550-2,200 ng ml-'.Values for terminal elimination rate constant, (X,) plasma clearance (CL), initial volume of distribution (V1) and volume of distribution at steady state (Vss) were calculated. For the healthy subjects, mean estimates of these parameters were X, = 0.062 ± 0.030 day-1, CL = 597 ± 238 ml min-, V1 = 0.66 ± 0.71 1 kg-" and Vss = 132 ± 50 1 kg-1For the group of malaria patients, the corresponding values were A, = 0.055 ± 0.032 day-1, CL = 535 ± 246 ml min-1, V1 = 0.74 ± 0.75 1 kg-1 and Vss = 136 ± 64 1 kg-1There was no statistically significant difference in the estimates for any parameter between groups (P -0.05). 4 Chloroquine concentrations in packed red blood cells consistently exceeded those in plasma and showed no consistent change with time throughout the period of study in either group. The median value for the red cell to plasma ratio was between 3 and 4 in each group. Peak red-cell concentrations were significantly higher than the equivalent plasma concentration in both groups. In the malaria patients the range of concentration was 1829-11052 ng ml-'. In the healthy volunteers, the range was 2410-4570 ng ml-'. were not statistically significant. There was no significant difference in the area under the sacked red-cell concentration vs time curve between the malaria patients (151637 + 85737 ng m-1' h) and healthy volunteers (100053 ± 42536 ng ml-1 h), when measured to infinite time.5 Various subjective side effects were reported in all participants. A small but significant fall from baseline systolic blood pressure 105 ± 6 mmHg was recorded, 2 h into the infusion (99 ± 9 mmHg), but baseline values had been regained by the end of the infusion (101 ± 10 mmHg). There was no significant rise in heart rate. However the minimum measured blood pressure and maximum recorded pulse in each subject were significantly different from the resting values. 6 Coincident with changes in blood pressure, there was, in both groups, a significant prolongation of the PR interval, QRS interval (88 ± 13 ms to 101 ± 17 ms) and an increase in T wave height (44 ± 13%). 7 These findings suggest that there are no major differences in the pharmacokinetics of chloroquine between the group of patients with vivax malaria studied here and a matched group of healthy volunteers. The cardiovascular effects of the drug are common to both groups, suggesting that the relationships between the pharmacokinetics of chloroquine are governed principally by the ...

3 Repeated dosing with primaquine had no effect on the mean pharmacokinetic parameters calculated for this drug. In contrast, individual pharmacokinetic parameters for some subjects exhibited gross and unpredictable changes after chronic dosage. 4 The carboxylic acid metabolite of primaquine accumulated in plasma after repeated dosing such that by day 14 of chronic dosing the mean AUC (0,24) for this metabolite was 74% greater than that obtained after acute administration of primaquine.