Stereoselective de-ethylation of chloroquine in rat liver microsomes

Abstract

A qualitative kinetic study on the stereoselective hepatic metabolism of chloroquine was undertaken by separately incubating chloroquine enantiomers with rat liver microsomes. The dependency of desethylchloroquine formation on NADPH suggests a cytochrome P-450 isozyme catalysed metabolism. Over a wide concentration range (1-300 microM), chloroquine metabolism appeared not to follow simple Michaelis-Menten kinetics. The enantiomeric ratio (R/S) of desethylchloroquine was dependent on concentration, and ranged from 8 at 1 microM to 1 at 300 microM. Mutual enantiomer--enantiomer interaction studies at low concentration (1-5 microM) revealed that the formation of (R)-desethylchloroquine was strongly inhibited by (S)-chloroquine. The findings of the present study support the hypothesis that a high-affinity/low capacity enzyme is capable of stereoselective discrimination. At this point, it remains to be proven whether stereoselective metabolism and enantiomer-enantiomer interactions affect the in vivo disposition of chloroquine.

Enantioselective determination of chloroquine and its n‐dealkylated metabolites in plasma using liquid‐phase microextraction and LC‐MS

“…As verified for mefloquine [25], another antimalarial drug, the enantioselective dispositon of CQ and DCQ in these animals was opposite of that noted in humans. Moreover, these findings are in good agreement with a published study about the enantioselective metabolism of CQ in rats [11]. As already pointed out by Augustijns and Verbeke [12], the enantiomers of BDCQ were not observed after a single administration of the drug.…”

“…In rabbits, a longer terminal half-life was seen for ( -)-(R)-CQ together with a statistically significant higher area under the concentration -time curve (AUC) for (+)-(S)-DCQ [10]. An enantioselective metabolism of CQ was noted in rat liver microsomes as well [11]. After single oral doses of the separate enantiomers or the racemic drug to human volunteers, an enantioselective disposition of CQ and DCQ was also observed [12,13].…”

Preparation of (−)-(R)-2-(2,3,4,5,6-pentafluorophenoxy)-2-(phenyl-d5)acetic acid: an efficient 1H NMR chiral solvating agent for direct enantiomeric purity evaluation of quinoline-containing antimalarial drugs

“…Several traditional, quinoline-containing antimalarial agents such as chloroquine 1, hydroxychloroquine 2, and mefloquine 3 are dispensed as racemates, while evidence indicates that the corresponding isolated enantiomers may have different pharmacodynamic, 6,7,11 toxicological, 8,10,13 and pharmacokinetic properties. 9,10,12,14 Thus, the chiral switch 15 approach (the use of single enantiomers in lieu of the corresponding racemate) might offer a straightforward way to safer and more efficacious drugs. salts of (À)-and (+)-2 with (+)-(S)-binaphthylphosphoric acid can be determined by monitoring the ratio of the two methyl doublets at 1.22 and 1.26 ppm.…”