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We report a case of a woman hospitalized after chloroquine overdose whose whole blood concentration on admission was 7.87 micrograms/ml. High blood concentrations of chloroquine induce cardiotoxicity and have been associated with death when they exceed 3.0 micrograms/ml. Early administration of massive doses of diazepam has been described to reduce the mortality due to chloroquine toxicity, but the protective mechanism has remained unknown. This patient was treated with diazepam (2.0 mg/kg over 30 min followed by a dosage of 1.0 to 2.0 mg/kg over 24 h), yet she remained awake despite the high plasma concentrations of diazepam and nordiazepam which would normally be associated with sedation. This suggests an antagonistic effect of chloroquine on the benzodiazepine-induced sedation due to an interaction between these drugs at their site of action.

Stereoselective pharmacokinetic properties of chloroquine were investigated in humans after a single oral dose of the separate enantiomers. The study was carried out according to a crossover experimental design with a washout period between the administration of each enantiomer. Total blood chloroquine concentrations were measured using an achiral high performance liquid chromatography method. Terminal half-life (t1/2 lambda z) and mean residence time (MRT) were longer for (R)-chloroquine (294h and 388h, respectively) than for (S)-chloroquine (236h and 272h, respectively). The total body clearance was lower for the (R)-enantiomer [136 +/- 38 ml/min (8.16 +/- 2.28 L/h)] than for the (S)-enantiomer [237 +/- 71 ml/min (14.22 +/- 4.26 L/h)]. Although the (R)-stereoisomer remained longer in the body, its volume of distribution (3410 +/- 720L) was lower than than that of (S)-chloroquine (4830 +/- 1490L). Protein binding was different for both chloroquine stereoisomers, with opposite preferential binding to human albumin and alpha 1-acid glycoprotein. Binding to total human plasma amounted to 66.6 +/- 3.3% for (S)-chloroquine and to 42.7 +/- 2.1% for the (R)-enantiomer. De-ethyl-chloroquine concentrations were also different for both enantiomers, resulting in a statistically significant increase in the AUC of (S)-de-ethyl-chloroquine (12.9 +/- 7.4 mg/L.h) compared with (R)-de-ethyl-chloroquine (6.29 +/- 2.18 mg/L.h). With a daily dosage regimen, the divergent pharmacokinetic behaviour of chloroquine enantiomers generates a calculated R:S ratio of blood concentrations amounting to 1:0.7 at steady-state. Insufficient information about stereoselective activity and toxicity of chloroquine stereoisomers prevent further conclusions about the clinical consequences of these pharmacokinetic differences.

Stereoselective pharmacokinetic properties of chloroquine (CAS 54-05-7) and desethylchloroquine were investigated in rabbits by administration of the separate enantiomers according to a cross-over design. The terminal half-life was longer for (R)-chloroquine than for (S)-chloroquine. A striking difference was revealed in the concentrations of metabolites. The levels of (R)-desethylchloroquine were higher than those of (S)-desethylchloroquine, resulting in a statistically significant higher AUC for the (R)-metabolite than for the (S)-metabolite.

Blood levels of racemic chloroquine and its main metabolites desethylchloroquine and bisdesethylchloroquine were measured in 29 patients treated chronically for rheumatoid arthritis. In six patients, the concentrations were followed during a one day dosage interval. There was considerable intersubject variability in the steady state blood concentrations of chloroquine (range 36.6 to 3895 ng.ml-1) and its two main biotransformation products; the latter represented, respectively, 47.7% and 12.9% of the concentration of chloroquine. This finding shows the need for further studies in view of the known toxic effects of chloroquine and the inevitable accumulation due to the exceptionally long residence time of the compound and its metabolites. The main requirement, which has not yet been met, for adding chloroquine to the list of drugs for which therapeutic drug monitoring is useful, is the lack of information about its mechanism of action, and consequently the dose-effect relationships of its therapeutic and toxic actions. Regular ophthalmic examination, in particular, is strongly recommended. The relatively high concentrations of desethylchloroquine and bisdesethylchloroquine found during chronic treatment show the need for more information about the therapeutic value and adverse effects of the metabolites.

Chloroquine is frequently used during pregnancy in malaria-endemic countries, but no data are available about fetal exposure to the drug. Prophylactic use during labour to obtain effective concentrations in the newborn is also documented. In the present study, the placental transfer of chloroquine was investigated in the pregnant, near-term sheep model. Chronic catheterization allowed blood sampling of maternal and fetal blood. Following a single intramuscular injection or intravenous infusion to the ewe, chloroquine was slowly distributed to the fetus. Peak concentrations in the fetus reached up to +/- 280 ng/ml within 2-4 h after administration while maximal concentrations in the mother reached up to 2,850 ng/ml. The terminal half-life of chloroquine in pregnant sheep was very long, amounting to 65.1 +/- 34.9 h (range 27.4-119 h). Tissue binding was high, as reflected by the extensive volume of distribution (V(area): 19.0 +/- 11.0 l/kg). Total clearance was equal to 3.42 +/- 0.60 ml/min/kg. The transfer rate of chloroquine from the mother to the fetus was low in all animals. So, the placenta is quite an effective barrier for the drug.