Stereoselective Pharmacokinetic Properties of Chloroquine and De-Ethyl-Chloroquine in Humans

Summary

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 (t_{½λz 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 that of (S)-chloroquine (4830 ± 1490L). Protein binding was different for both chloroquine stereoisomers, with opposite preferential binding to human albumin and α₁-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.