Stereoselective de-ethylation of chloroquine in rat liver microsomes

A qualitative kinetic study on the stereoselective hepatic metabolism of ch loroquine was undertaken by separately incubating chloroquine enantiomers w ith rat liver microsomes. The dependency of desethylchloroquine formation o n NADPH suggests a cytochrome P-450 isozyme catalysed metabolism. Over a wi de concentration range (1-300 mu M), chloroquine metabolism appeared not to follow simple Michaelis-Menten kinetics. The enantiomeric ratio (R/S) of d esethylchloroquine was dependent on concentration, and ranged from 8 at 1 m u M to 1 at 300 mu M. Mutual enantiomer-enantiomer interaction studies at l ow concentration (1-5 mu M) revealed that the formation of (R)-desethylchlo roquine was strongly inhibited by (S)-chloroquine. The findings of the pres ent study support the hypothesis that a high-affinity/low capacity enzyme i s capable of stereoselective discrimination. At this point, it remains to b e proven whether stereoselective metabolism and enantiomer-enantiomer inter actions affect the in vivo disposition of chloroquine.