Stereoselective de-ethylation of chloroquine in rat liver microsomes.

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.