Asymmetric redox reactions in human liver stereoselective oxidation of optically active dihydrohaloperidols, dihydrobromoperidols and stereospecific reduction of haloperidol and bromoperidol.
The stereoselective oxidation of dihydrohaloperidols (3a, b) and dihydrobromoperidols (4a, b), which are the main metabolites of haloperidol (1) and bromoperidol (2) in humans, respectively, were pharmacokinetically investigated using human liver microsomes and human cytochrome P450(CYP) isoenzymes expressed in the human cell line. The oxidation rates of the (R)-isomers (3a and 4a) in the human liver microsomes were faster than those of the (S)-isomers (3b and 4b), and the R/S enantiomeric ratios of 3 and 4 for intrinsic clearance (Vmax/Km) were 1.40 and 3.10, respectively, showing that stereoselective oxidation occurred in human liver. Concerning the involvement of the CYP isoenzymes in this oxidative pathway, the (R)-isomers (3a and 4a) were catalyzed by both CYP3A4 and CYP2D6, however, the (S)-isomers (3b and 4b) were catalyzed only by CYP3A4.
Takeshita
M
M
Department of Pharmaceutical Sciences, Tohoku Pharmaceutical University, Sendai, Japan. mtake@tohoku-pharm.ac.jp
Miura
M
M
Ohkubo
T
T
Sugawara
K
K
D002851:Chromatography, High Pressure Liquid; D019389:Cytochrome P-450 CYP2D6 / Q000378:metabolism; D051544:Cytochrome P-450 CYP3A; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism; D003600:Cytosol / Q000378:metabolism; D006220:Haloperidol / Q000031:analogs & derivatives* / Q000737:chemistry / Q000493:pharmacokinetics*; D006801:Humans; D008862:Microsomes, Liver / Q000201:enzymology / Q000378:metabolism*; D006899:Mixed Function Oxygenases / Q000378:metabolism; D010084:Oxidation-Reduction; D013237:Stereoisomerism
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; D006220:Haloperidol; C006820:bromperidol