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Research ArticleArticle

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
Drug Metabolism and Disposition October 2001, 29 (10) 1263-1268;
Norio Yasui-Furukori
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Mats Hidestrand
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Edoardo Spina
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Gabriella Facciolá
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Maria Gabriella Scordo
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Gunnel Tybring
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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.

Footnotes

  • This study has been supported by grants from Björn Lindström Memorial Found, the Swedish Medical Research Council (3902), and Karolinska Institutet.

  • Abbreviations used are::
    HPLC
    high pressure liquid chromatography
    P-450 or CYP
    cytochrome P-450
    CLint
    intrinsic clearance
    • Received April 12, 2001.
    • Accepted June 4, 2001.
  • The American Society for Pharmacology and Experimental Therapeutics
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Drug Metabolism and Disposition: 29 (10)
Drug Metabolism and Disposition
Vol. 29, Issue 10
1 Oct 2001
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Research ArticleArticle

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
Drug Metabolism and Disposition October 1, 2001, 29 (10) 1263-1268;

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Research ArticleArticle

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
Drug Metabolism and Disposition October 1, 2001, 29 (10) 1263-1268;
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