The oxidative metabolism of dimemorfan by human cytochrome P450 enzymes |
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| Authors: | Yueh-Ching Chou Yu-Ting Chung Tsung-Yun Liu Szu-Yu Wang Gar-Yang Chau Chin-Wen Chi Pavel Souček Kristopher W. Krausz Harry V. Gelboin Chen-Hsen Lee Yune-Fang Ueng |
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| Affiliation: | 1. Pharmacy Department, Taipei Veterans General Hospital, Taipei, Taiwan, ROC;2. Department of Pharmacology, National Yang-Ming University, Taipei, Taiwan, ROC;3. School of Pharmacy, Taipei Medical University, Taipei, Taiwan, ROC;4. Institute of Environmental Health, National Yang-Ming University, Taipei, Taiwan, ROC;5. Medical Research and Education, Taipei Veterans General Hospital, Taipei, Taiwan, ROC;6. Department of Surgery, Taipei Veterans General Hospital, Taipei, Taiwan, ROC;7. Department of Toxicogenomics, National Institute of Public Health, Praha, Czech Republic;8. Laboratory of Metabolism, National Institute of Health, Bethesda, Maryland;9. Taipei Veterans General Hospital, Taipei, Taiwan, ROC;10. National Yang-Ming University, Taipei, Taiwan, ROC;11. National Research Institute of Chinese Medicine, Taipei, Taiwan, ROC;12. Graduate Institute of Medical Sciences, Taipei Medical University, Taipei, Taiwan, ROC |
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| 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 (S50) 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 Km value of 0.02 mM in forming M1. CYP2B6, CYP2C9, and CYP2C19 had the Km or S50 values smaller than those (1 mM) of CYP2D6 and CYP3A4 in forming M2. These results indicated the participation of multiple P450 forms in DFO. © 2009 Wiley-Liss, Inc. and the American Pharmacists Association J Pharm Sci 99:1063–1077, 2010 |
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