Pharmacokinetic drug interaction potential of risperidone with cytochrome p450 isozymes as assessed by the dextromethorphan, the caffeine, and the mephenytoin test.
Two published case reports showed that addition of risperidone (1 and 2 mg/d) to a clozapine treatment resulted in a strong increase of clozapine plasma levels. As clozapine is metabolized by cytochrome P450 isozymes, a study was initiated to assess the in vivo interaction potential of risperidone on various cytochrome P450 isozymes. Eight patients were phenotyped with dextromethorphan (CYP2D6), mephenytoin (CYP2C19), and caffeine (CYP1A2) before and after the introduction of risperidone. Before risperidone, all eight patients were phenotyped as being extensive metabolizers of CYP2D6 and CYP2C19. Risperidone at dosages between 2 and 6 mg/d does not appear to significantly inhibit CYP1A2 and CYP2C19 in vivo (median plasma paraxanthine/caffeine ratios before and after risperidone: 0.65, 0.69; p = 0.89; median urinary (S)/(R) mephenytoin ratios before and after risperidone:0.11, 0.12; p = 0.75). Although dextromethorphan metabolic ratio is significantly increased by risperidone (median urinary dextromethorphan/dextrorphan ratios before and after risperidone: 0.010, 0.018; p = 0.042), risperidone can be considered a weak in vivo CYP2D6 inhibitor, as this increase is modest and none of the eight patients was changed from an extensive to a poor metabolizer. The reported increase of clozapine concentrations by risperidone can therefore not be explained by an inhibition of CYP1A2, CYP2D6, CYP2C19 or by any combination of the three.
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Unit of Biochemistry and Clinical Psychopharmacology, University Department of Adult Psychiatry, Cery Hospital, CH-Prilly-Lausanne, Switzerland. Chin.Eap@inst.hospvd.ch
Bondolfi
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Zullino
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Bryois
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Fuciec
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Savary
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Jonzier-Perey
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Baumann
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D000328:Adult; D014150:Antipsychotic Agents / Q000493:pharmacokinetics*; D001189:Aryl Hydrocarbon Hydroxylases; D002110:Caffeine / Q000493:pharmacokinetics*; D065731:Cytochrome P-450 CYP2C19; D019389:Cytochrome P-450 CYP2D6 / Q000502:physiology*; D065690:Cytochrome P-450 CYP2D6 Inhibitors; D051544:Cytochrome P-450 CYP3A; D065607:Cytochrome P-450 Enzyme Inhibitors; D003577:Cytochrome P-450 Enzyme System / Q000502:physiology*; D003915:Dextromethorphan / Q000493:pharmacokinetics*; D004347:Drug Interactions; D005260:Female; D006801:Humans; D008297:Male; D008617:Mephenytoin / Q000493:pharmacokinetics*; D008875:Middle Aged; D006899:Mixed Function Oxygenases / Q000037:antagonists & inhibitors / Q000502:physiology*; D010641:Phenotype; D018967:Risperidone / Q000493:pharmacokinetics*
D014150:Antipsychotic Agents; D065690:Cytochrome P-450 CYP2D6 Inhibitors; D065607:Cytochrome P-450 Enzyme Inhibitors; D002110:Caffeine; D003915:Dextromethorphan; D003577:Cytochrome P-450 Enzyme System; D006899:Mixed Function Oxygenases; D001189:Aryl Hydrocarbon Hydroxylases; C045793:CYP2C19 protein, human; C104464:CYP3A protein, human; D065731:Cytochrome P-450 CYP2C19; D019389:Cytochrome P-450 CYP2D6; D051544:Cytochrome P-450 CYP3A; D018967:Risperidone; D008617:Mephenytoin