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 antipsychotic drug, to form 4-fluorobenzoyl-propionic acid (FBPA) in hepatic microsomes from 8-week-old male Sprague-Dawley rats and to investigate whether an inhibitor or an inducer of CYP3A affects BP pharmacokinetics in rat. 2. In an in vitro study, only troleandomycin showed marked inhibition of FBPA formation among several specific CYP isozyme inhibitors studied including 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 average control value by 7-day treatment with erythromycin, a CYP3A inhibitor, and shortened to 58% of the control by 2-day treatment with dexamethasone, a CYP3A inducer. BP clearance was reduced to 68% of the control by erythromycin 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 activity would affect the pharmacokinetics of BP.
Watanabe
M
M
Department of Pharmacology, St Marianna University School of Medicine, Kawasaki, Kanagawa, Japan. m4wata@marianna-u.ac.jp
Tateishi
T
T
Tanaka
M
M
Kumai
T
T
Kobayashi
S
S
D000818:Animals; D001189:Aryl Hydrocarbon Hydroxylases; D051544:Cytochrome P-450 CYP3A; D065607:Cytochrome P-450 Enzyme Inhibitors; D003577:Cytochrome P-450 Enzyme System / Q000187:drug effects / Q000276:immunology / Q000378:metabolism*; D003907:Dexamethasone / Q000494:pharmacology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D004917:Erythromycin / Q000494:pharmacology; D006207:Half-Life; D006220:Haloperidol / Q000031:analogs & derivatives* / Q000378:metabolism / Q000493:pharmacokinetics; D007106:Immune Sera / Q000494:pharmacology; D008297:Male; D008862:Microsomes, Liver / Q000187:drug effects / Q000378:metabolism*; D010089:Oxidoreductases, N-Demethylating / Q000187:drug effects / Q000378:metabolism*; D011422:Propionates / Q000378:metabolism; D011803:Quinine / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D013250:Steroid Hydroxylases / Q000037:antagonists & inhibitors / Q000276:immunology; D013806:Theophylline / Q000031:analogs & derivatives / Q000494:pharmacology; D014217:Troleandomycin / Q000494:pharmacology
D065607:Cytochrome P-450 Enzyme Inhibitors; D004791:Enzyme Inhibitors; D007106:Immune Sera; D011422:Propionates; C080346:beta-(4-fluorobenzoyl)propionic acid; D004917:Erythromycin; D003907:Dexamethasone; D003577:Cytochrome P-450 Enzyme System; D011803:Quinine; D013806:Theophylline; C050131:furafylline; D014217:Troleandomycin; D013250:Steroid Hydroxylases; D001189:Aryl Hydrocarbon Hydroxylases; D051544:Cytochrome P-450 CYP3A; C022657:steroid hormone 6-beta-hydroxylase; D010089:Oxidoreductases, N-Demethylating; D006220:Haloperidol; C006820:bromperidol