@article {Yasui-Furukori1263, author = {Norio Yasui-Furukori and Mats Hidestrand and Edoardo Spina and Gabriella Facciol{\'a} and Maria Gabriella Scordo and Gunnel Tybring}, title = {Different Enantioselective 9-Hydroxylation of Risperidone by the Two Human CYP2D6 and CYP3A4 Enzymes}, volume = {29}, number = {10}, pages = {1263--1268}, year = {2001}, publisher = {American Society for Pharmacology and Experimental Therapeutics}, abstract = {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 α-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. The American Society for Pharmacology and Experimental Therapeutics}, issn = {0090-9556}, URL = {https://dmd.aspetjournals.org/content/29/10/1263}, eprint = {https://dmd.aspetjournals.org/content/29/10/1263.full.pdf}, journal = {Drug Metabolism and Disposition} }