Different enantioselective 9-hydroxylation of risperidone by the two human CYP2D6 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-hydroxyrisperidone might be formed, and the aim of this study was to evaluate the importance of CYP2D6 and CYP3A4/CYP3A5 in the formation of these two enantiomers in human liver microsomes and in recombinantly expressed enzymes. The enantiomers of 9-hydroxyrisperidone were analyzed with high pressure liquid chromatography using a chiral -1 acid glycoprotein column. A much higher formation rate was observed for ()-9-hydroxyrisperidone than for ()-9-hydroxyrisperidone in microsomes prepared from six individual livers. The formation of ()-9-hydroxyrisperidone was strongly inhibited by quinidine, 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 formation 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 clearly suggest that CYP2D6 plays a predominant role in ()-9- hydroxylation of risperidone, the major metabolic pathway in clinical conditions, whereas CYP3A catalyzes the formation of the ()-9- hydroxymetabolite. Further studies are required to evaluate the pharmacological/ toxic activity of both enantiomers.