Effects of itraconazole on the steady-state plasma concentrations of bromperidol and reduced bromperidol in schizophrenic patients.
BACKGROUND
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.
Furukori
H
H
Department of Neuropsychiatry, Hirosaki University School of Medicine, Japan.
Kondo
T
T
Yasui
N
N
Otani
K
K
Tokinaga
N
N
Nagashima
U
U
Kaneko
S
S
Inoue
Y
Y
D000328:Adult; D000368:Aged; D051544:Cytochrome P-450 CYP3A; D065607:Cytochrome P-450 Enzyme Inhibitors; D004347:Drug Interactions; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D005260:Female; D006220:Haloperidol / Q000031:analogs & derivatives / Q000493:pharmacokinetics; D006801:Humans; D017964:Itraconazole / Q000494:pharmacology*; D008875:Middle Aged; D006899:Mixed Function Oxygenases / Q000037:antagonists & inhibitors*; D012559:Schizophrenia / Q000378:metabolism*
D065607:Cytochrome P-450 Enzyme Inhibitors; D004791:Enzyme Inhibitors; D017964:Itraconazole; D006899:Mixed Function Oxygenases; C104464:CYP3A protein, human; D051544:Cytochrome P-450 CYP3A; C510163:CYP3A4 protein, human; D006220:Haloperidol; C006820:bromperidol