Different enantioselective 9-hydroxylation of risperidone by the two humanCYP2D6 and CYP3A4 enzymes

The antipsychotic agent risperidone, is metabolized by different cytochrome P-450 (CYP) enzymes, including CYP2D6, to the active 9-hydroxyrisperidone, which is the major metabolite in plasma. Two enantiomers, (+)- and (-)-9-h ydroxyrisperidone might be formed, and the aim of this study was to evaluat e the importance of CYP2D6 and CYP3A4/CYP3A5 in the formation of these two enantiomers in human liver microsomes and in recombinantly expressed enzyme s. The enantiomers of 9-hydroxyrisperidone were analyzed with high pressure liquid chromatography using a chiral alpha -1 acid glycoprotein column. A much higher formation rate was observed for (+)-9-hydroxyrisperidone than f or (-)-9-hydroxyrisperidone in microsomes prepared from six individual live rs. The formation of (+)-9-hydroxyrisperidone was strongly inhibited by qui nidine, a potent CYP2D6 inhibitor, whereas ketoconazole, a CYP3A4 inhibitor , strongly inhibited the formation of (-)-9-hydroxyrisperidone. Recombinant human CYP2D6 produced only (+)-9-hydroxyrisperidone, whereas a lower forma tion rate of both enantiomers was detected with expressed CYP3A4 and CYP3A5 . In vivo data from 18 patients during treatment with risperidone indicate that the plasma concentration of the (+)-enantiomer is higher than that of the (-)-enantiomer in extensive metabolizers of CYP2D6. These findings clea rly suggest that CYP2D6 plays a predominant role in (+)-9-hydroxylation of risperidone, the major metabolic pathway in clinical conditions, whereas CY P3A catalyzes the formation of the (-)-9-hydroxymetabolite. Further studies are required to evaluate the pharmacological/toxic activity of both enanti omers.