PT  - JOURNAL ARTICLE
AU  - Norio Yasui-Furukori
AU  - Mats Hidestrand
AU  - Edoardo Spina
AU  - Gabriella Facciolá
AU  - Maria Gabriella Scordo
AU  - Gunnel Tybring
TI  - Different Enantioselective 9-Hydroxylation of Risperidone by the Two Human CYP2D6 and CYP3A4 Enzymes
DP  - 2001 Oct 01
TA  - Drug Metabolism and Disposition
PG  - 1263--1268
VI  - 29
IP  - 10
4099  - http://dmd.aspetjournals.org/content/29/10/1263.short
4100  - http://dmd.aspetjournals.org/content/29/10/1263.full
SO  - Drug Metab Dispos2001 Oct 01; 29
AB  - 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