Effects of itraconazole on the steady-state plasma concentrations of bromperidol and reduced bromperidol in schizophrenic patients

Rationale: A previously reported pharmacokinetic interaction between bromperidol and carbamazepine, an inducer of cytochrome P450 (CYP) 3A4, suggests possible involvement of CYP3A4 in the metabolism of bromperidol. Objective: We investigated pharmacokinetic interaction between bromperidol and itraconazole, a potent inhibitor of CYP3A4, to clarify the involvement of CYP3A4 in the metabolism of bromperidol and its reduced metabolite. Methods: Itraconazole 200 mg/day for 7 days was coadministered to eight schizophrenic patients treated with a fixed dose of bromperidol 12 or 24 mg/day for at least 2 weeks. Blood samples were taken before and 1 week after itraconazole coadministration and 1 week after its discontinuation, together with clinical assessments using the Brief Psychiatric Rating Scale (BPRS) and the Udvalg for Kliniske Undersøgelser (UKU) Side Effect Rating Scale. Results: Plasma concentrations of bromperidol during itraconazole coadministration (16.7±4.9 ng/ml) were significantly higher (P<0.01) than before itraconazole coadministration (8.9±4.4 ng/ml) and 1 week after its discontinuation (9.9±4.3 ng/ml). Plasma concentrations of reduced bromperidol during itraconazole coadministration (3.6±2.9 ng/ml) were significantly higher (P<0.01) than before itraconazole coadministration (1.8±1.3 ng/ml). No changes were observed in BPRS and UKU scores throughout the study. Conclusions: The pharmacokinetic interaction between bromperidol and itraconazole is probably due to the inhibitory effect of itraconazole on the metabolism of bromperidol. This study provides in vivo evidence of involvement of CYP3A4 in the metabolism of bromperidol and reduced bromperidol.