Role of CYP3A in bromperidol metabolism in rat in vitro and in vivo

1. The aim was to identify whether CYP3A metabolizes bromperidol (BP), an a ntipsychotic drug, to form 4-fluorobenzoyl-propionic acid (FBPA) in hepatic microsomes from 8-week-old male Sprague-Dawley rats and to investigate whe ther an inhibitor or an inducer of CYP3A affects BP pharmacokinetics in rat . 2. In an in vitro study, only troleandomycin showed marked inhibition of FB PA formation among several specific CYP isozyme inhibitors studied includin g troleandomycin, diethyldithiocarbamate, furafylline and quinine. Anti-rat CYP3A2 serum inhibited FBPA formation by 80 %, whereas other anti-rat CYP sera (1A1, 1A2, 2B1, 2C11, 2E1) only slightly inhibited it. 3. In a pharmacokinetic study, BP half-life was prolonged to 137% of the av erage control value by 7-day treatment with erythromycin, a CYP3A inhibitor , and shortened to 58 % of the control by 2-day treatment with dexamethason e, a CYP3A inducer. BP clearance was reduced to 68 % of the control by eryt hromycin and was increased to 145 % of control by dexamethasone. 4. These results suggested that BP biotransformation is catalysed mainly by CYP3A to form FBPA in rat and that the modification of this enzyme activit y would affect the pharmacokinetics of BP.