Effects of itraconazole on the steady-state plasma concentrations of haloperidol and its reduced metabolite in schizophrenic patients: In vivo evidence of the involvement of CYP3A4 for haloperidol metabolism

The effects of itraconazole, a potent inhibitor of cytochrome P450 (CYP) 3A 4, on the steady-state plasma concentrations of haloperidol and reduced hal operidol were examined in schizophrenic patients. Thirteen schizophrenic pa tients treated with haloperidol 12 or 24 mg/day received 200 mg/day of itra conazole for 7 days. Plasma concentrations of haloperidol and reduced halop eridol were measured by high-performance liquid chromatography together wit h clinical assessment by the Brief Psychiatric Rating Scale (BPRS) and the Udvalg for Kliniske Undersogelser side effect rating scale just before and during itraconazole treatment and 1 week after its discontinuation. Plasma concentrations of haloperidol and reduced haloperidol during the itraconazo le treatment (16.9 +/- 11.2 and 6.1 +/- 6.6 ng/mL, respectively) were signi ficantly (p < 0.01) higher than those observed before itraconazole treatmen t (13.0 +/- 7.9 and 4.9 +/- 5.1 ng/mL) or 1 week after its discontinuation (13.5 +/- 8.2 and 4.9 +/- 5.0 ng/mL). No change was found in clinical sympt oms assessed by BPRS, whereas neurologic side effects were significantly (p < 0.05) increased during itraconazole coadministration. The elevated plasm a concentrations of haloperidol and reduced haloperidol during itraconazole coadministration were likely due to the inhibitory effects of itraconazole on the metabolism of haloperidol and reduced haloperidol. Thus, this study may provide in vivo evidence of involvement of CYP3A4 in the metabolism of haloperidol and possibly in that of reduced haloperidol. Deterioration of neurologic side effects during itraconazole treatment may result from the i ncreased plasma concentrations of haloperidol and reduced haloperidol durin g itraconazole treatment.