Effect of CYP2D6 genotype on pharmacokinetic interactions with psychotropic drugs

Abstract

Most of neuroleptics has been reported as a substrate of not only cytochrome P450 (CYP) 2D6, but also CYP3A4. Thus, the effect of CYP2D6 genotype on pharmacokinetic interactions with a CYP3A4 inhibitor or inducer was examined in Japanese patients with psychiatric disorders who were treated with neuroleptics. Thirteen schizophrenic patients treated with haloperidol at 12 or 24 mg/day (Group 1) and and another nine treated with risperidone at 6 mg/day (Group 2) participated in the studies. Itraconazole (CYP3A4 inhibitor) and carbamazepine (CYP3A4 inducer) were coadministered in Groups 1 and 2, respectively. Blood samplings were performed before and after the coadministration, and plasma drug concentrations were determined using HPLC. CYP2D6 genotypes were identified using PCR method. Itraconazole and carbamazepine significantly altered plasma drug concentrations in Groups 1 and 2, respectively. There was no difference in the inhibition degree by itraconazole between different CYP2D6 genotypes in Group 1. In contrast, significant difference was found in the induction degree by carbamazepine between different CYP2D6 genotypes in Group 2. The present studies, thus, show that CYP2D6 genotype has an impact on drug interaction with risperidone, but not haloperidol. These findings suggest that CYP2D6 predominantly involved in risperidone metabolism, compared with haloperidol.