Different enantioselective 9-hydroxylation of risperidone by the two human CYP2D6 and CYP3A4 enzymes.
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Yasui-Furukori N, Hidestrand M, Spina E, Facciola G, Scordo MG, Tybring G
Different enantioselective 9-hydroxylation of risperidone by the two human CYP2D6 and CYP3A4 enzymes.
Drug Metab Dispos. 2001 Oct;29(10):1263-8.
- PubMed ID
- 11560868 [ View in PubMed]
- 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 alpha-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.
DrugBank Data that Cites this Article
- Drug Enzymes
Drug Enzyme Kind Organism Pharmacological Action Actions Paliperidone Cytochrome P450 3A5 Protein Humans UnknownSubstrateDetails Risperidone Cytochrome P450 2D6 Protein Humans UnknownSubstrateInhibitorDetails