Cytochrome P450 3A inhibitor itraconazole affects plasma concentrations of risperidone and 9-hydroxyrisperidone in schizophrenic patients.

Background And Objective: Despite the belief that cytochrome P450 (CYP) 2D6 alone is responsible for the metabolism of risperidone, several studies suggest that CYP3A may be involved. The aim of this study was to evaluate the effect of itraconazole, a CYP3A inhibitor, on the plasma concentrations of risperidone and 9-hydroxyrisperidone in schizophrenic patients in relation to CYP2D6 genotype.

Methods: Nineteen schizophrenic patients treated with 2 to 8 mg/d of risperidone received 200 mg/d of itraconazole for a week. Plasma concentrations of risperidone and 9-hydroxyrisperidone were measured immediately before and after itraconazole treatment, as well as at 1 week after itraconazole treatment was stopped, together with clinical assessment by use of the Udvalg for Kliniske Undersøgelser Side Effect Rating Scale and the Brief Psychiatric Rating Scale.

Results: Dose-normalized plasma concentrations of risperidone and 9-hydroxyrisperidone before itraconazole treatment (0.9 +/- 0.8 ng.mL(-1).mg(-1) and 6.9 +/- 3.3 ng.mL(-1).mg(-1), respectively) were significantly elevated after itraconazole treatment (1.6 +/- 1.3 ng.mL(-1).mg(-1) and 11.3 +/- 4.5 ng.mL(-1).mg(-1)) and decreased 1 week after its discontinuation (1.0 +/- 0.8 ng.mL(-1).mg(-1) and 7.2 +/- 3.7 ng.mL(-1).mg(-1)) (P < .01). However, the ratio of risperidone/9-hydroxyrisperidone, an index of CYP2D6 activity, did not differ before itraconazole treatment (0.14 +/- 0.13), after itraconazole treatment (0.15 +/- 0.13), and 1 week after discontinuation (0.14 +/- 0.13) (P > .05). Itraconazole increased the concentrations of risperidone by 69% (P < .001) and 75% (P < .01) in CYP2D6 extensive and poor metabolizers, respectively. In addition, the active moiety (risperidone plus 9-hydroxyrisperidone) also increased similarly, by 71% (P < .001) and 73% (P < .05), respectively, with itraconazole, without a significant difference between CYP2D6 genotypes. The scores on the Brief Psychiatric Rating Scale decreased significantly but only by 6% after itraconazole treatment (P < .05); however, the scores on the Udvalg for Kliniske Undersøgelser Side Effect Rating Scale were not changed.

Conclusions: Our results provide in vivo evidence of the involvement of CYP3A in the disposition of risperidone and 9-hydroxyrisperidone. In addition to CYP2D6, treatment with CYP3A inhibitor(s) including itraconazole may influence clinical symptoms and risperidone side effects.