title: The oxidative metabolism of dimemorfan by human cytochrome P450 enzymes.
abstract: To characterize the human cytochrome P450 (P450) forms involved in dimemorfan oxidation (DFO), human liver microsomes, and recombinant P450s were investigated. Liquid chromatography-mass spectral analysis suggested that metabolite (M)1 ([M + H](+) m/z at 272.200) and M2 ([M + H](+) m/z at 242.190) were d-3-hydroxymethyl-N-methylmorphinan and d-3-methylmorphinan, respectively. Kinetic analyses of microsomal DFO showed that the substrate concentration showing a half-maximal velocity (S(50)) of M1 formation was less than that of M2. Microsomal M1 and M2 formation activities correlated significantly with the CYP2D6 marker, dextromethorphan O-demethylation activity. The M2 formation activity was also correlated with the CYP3A4 marker, nifedipine oxidation activity. Microsomal M1 and M2 formation was most sensitive to the inhibition by a CYP2D6 inhibitor, paroxetine and a CYP3A4 inhibitor, ketoconazole, respectively. The immunoinhibition-defined P450 contributions indicated the participation of CYP2C9, CYP2C19, and CYP2D6 in the M1 formation and CYP2B6, CYP2C9, CYP2C19, CYP2D6, and CYP3A4 in the M2 formation. Among recombinant P450s, CYP2D6 had the highest intrinsic clearance with a K(m) value of 0.02 mM in forming M1. CYP2B6, CYP2C9, and CYP2C19 had the K(m) or S(50) values smaller than those (1 mM) of CYP2D6 and CYP3A4 in forming M2. These results indicated the participation of multiple P450 forms in DFO.
authors: Pharmacy Department, Taipei Veterans General Hospital, Taipei, Taiwan, ROC.
authors: Yueh-Ching
authors: YC
authors: Chou
authors: Yu-Ting
authors: YT
authors: Chung
authors: Tsung-Yun
authors: TY
authors: Liu
authors: Szu-Yu
authors: SY
authors: Wang
authors: Gar-Yang
authors: GY
authors: Chau
authors: Chin-Wen
authors: CW
authors: Chi
authors: Pavel
authors: P
authors: Soucek
authors: Kristopher W
authors: KW
authors: Krausz
authors: Harry V
authors: HV
authors: Gelboin
authors: Chen-Hsen
authors: CH
authors: Lee
authors: Yune-Fang
authors: YF
authors: Ueng
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D000911:Antibodies, Monoclonal / Q000494:pharmacology; D000996:Antitussive Agents / Q000493:pharmacokinetics*; D002851:Chromatography, High Pressure Liquid; D065607:Cytochrome P-450 Enzyme Inhibitors; D003577:Cytochrome P-450 Enzyme System / Q000235:genetics / Q000378:metabolism*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005260:Female; D006801:Humans; D007527:Isoenzymes / Q000235:genetics / Q000378:metabolism; D007700:Kinetics; D008297:Male; D013058:Mass Spectrometry; D008862:Microsomes, Liver / Q000378:metabolism; D008875:Middle Aged; D009019:Morphinans / Q000493:pharmacokinetics*; D010084:Oxidation-Reduction; D010957:Plasmids / Q000235:genetics; D011994:Recombinant Proteins / Q000737:chemistry / Q000378:metabolism
chemical_list: D000911:Antibodies, Monoclonal; D000996:Antitussive Agents; D065607:Cytochrome P-450 Enzyme Inhibitors; D004791:Enzyme Inhibitors; D007527:Isoenzymes; D009019:Morphinans; D011994:Recombinant Proteins; C012621:dimemorfan; D003577:Cytochrome P-450 Enzyme System