title: Involvement of CYP3A4 and CYP2D6 in the metabolism of haloperidol.
abstract: 1. Human cytochrome P450 (CYP) isoenzymes expressed in a human cell line were used to elucidate their involvement in the metabolism of haloperidol (HAL). 2. It was found that CYP3A4 catalyzes the metabolism of HAL to HAL 1,2,3,6-tetrahydropyridine (HTP). HTP is further metabolized to HAL pyridinium (HP+) by both CYP3A4 and CYP2D6. 3. CYP3A4 and CYP2D6 are also responsible for the N-dealkylation of HAL. The N-dealkylation of reduced HAL (RH) was observed, which is catalyzed by CYP3A4. In addition, CYP3A4 also catalyzes the oxidation of RH back to HAL. 4. These results are discussed in terms of the metabolic interactions of HAL with other drugs and how this knowledge may be used to reduce the movement disorders induced by HAL.
authors.affiliation: Department of Psychiatry, University of Alberta, Edmonton, Canada.
authors.forename: J
authors.initials: J
authors.lastname: Fang
authors.forename: G B
authors.initials: GB
authors.lastname: Baker
authors.forename: P H
authors.initials: PH
authors.lastname: Silverstone
authors.forename: R T
authors.initials: RT
authors.lastname: Coutts
mesh_terms: D001711:Biotransformation; D002460:Cell Line; D019389:Cytochrome P-450 CYP2D6 / Q000378:metabolism*; D051544:Cytochrome P-450 CYP3A; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism*; D003579:Cytochrome Reductases / Q000378:metabolism; D004347:Drug Interactions; D006220:Haloperidol / Q000009:adverse effects / Q000493:pharmacokinetics*; D006801:Humans; D007700:Kinetics; D006899:Mixed Function Oxygenases / Q000378:metabolism*; D009069:Movement Disorders / Q000209:etiology / Q000517:prevention & control; D010084:Oxidation-Reduction
chemical_list: D003577:Cytochrome P-450 Enzyme System; D006899:Mixed Function Oxygenases; C104464:CYP3A protein, human; D019389:Cytochrome P-450 CYP2D6; D051544:Cytochrome P-450 CYP3A; C510163:CYP3A4 protein, human; D003579:Cytochrome Reductases; D006220:Haloperidol