Vol. 29, Issue 10, 1263-1268, October 2001

Different Enantioselective 9-Hydroxylation of Risperidone by the Two Human CYP2D6 and CYP3A4 Enzymes

Norio Yasui-Furukori, Mats Hidestrand, Edoardo Spina, Gabriella Facciolá, Maria Gabriella Scordo, and Gunnel Tybring

Department of Medical Laboratory Science & Technology, Division of Clinical Pharmacology, Karolinska Institutet, Huddinge University Hospital, Stockholm, Sweden (N.Y.-F., G.T.); Department of Environmental Medicine, Division of Molecular Toxicology, Karolinska Institutet, Stockholm, Sweden (M.H.); and Department of Clinical and Experimental Medicine and Pharmacology, Section of Pharmacology, University of Messina, Messina, Italy (E.S., G.F., M.G.S.)

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.