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 (I and 2 mg/ d) to a clozapine treatment resulted in a strong increase of clozapine plas ma levels. As clozapine is metabolized by cytochrome P450 isozymes, a study was initiated to assess the in vivo interaction potential of risperidone o n various cytochrome P450 isozymes. Eight patients were phenotyped with dex tromethorphan (CYP2D6), mephenytoin (CYP2C19), and caffeine (CYP1A2) before and after the introduction of risperidone. Before risperidone, all eight p atients were phenotyped as being extensive metabolizers of CYP2D6 and CYP2C 19. Risperidone at dosages between 2 and 6 mg/d does not appear to signific antly inhibit CYP1A2 and CYP2C19 in vivo (median plasma paraxanthine/caffei ne ratios before and after risperidone: 0.65, 0.69; p = 0.89; median urinar y (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 a nd after risperidone: 0.010, 0.018; p = 0.042), risperidone can be consider ed 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 com bination of the three.