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.
Augustijns
P
P
Laboratorium Farmacotechnologie en Biofarmacie, O&N, Gasthuisberg, Belgium.
Peeters
L
L
Croes
K
K
Verbeeck
R K
RK
D000818:Animals; D002738:Chloroquine / Q000378:metabolism*; D002851:Chromatography, High Pressure Liquid; D004305:Dose-Response Relationship, Drug; D066298:In Vitro Techniques; D008862:Microsomes, Liver / Q000378:metabolism*; D009249:NADP / Q000737:chemistry; D051381:Rats; D017208:Rats, Wistar; D013237:Stereoisomerism
D009249:NADP; D002738:Chloroquine