文献类型： 外文期刊

作者： Kong, L. M. ¹ ; Qian, M. R. ² ; Hu, H. H. ¹ ; Xu, S. Y. ¹ ; Yu, L. S. ¹ ; Jiang, H. D. ¹ ; Chen, S. Q. ¹ ; Zeng, S. ¹ ;

作者机构： 1.Zhejiang Univ, Dept Pharmaceut Anal & Drug Metab, Coll Pharmaceut Sci, Hangzhou 310058, Zhejiang, Peoples R China

2.Zhejiang Acad Agr Sci, Inst Qual Stand Agr Prod, Hangzhou, Zhejiang, Peoples R China

期刊名称：PHARMAZIE （ 影响因子：1.267； 五年影响因子：1.441 ）

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收录情况： SCI

摘要： Polymorphisms of the cytochrome P450 2D6 (CYP2D6) gene play a major role in pharmacokinetic variability in human, while CYP2D6*10 is an important subtype in Asian people. In this study, the co-expression enzyme of human recombinant CYPOR, CYPb5 and CYP2D6.1 or CYP2D6.10 with the Bac-to-Bac? system in baculovirus-infected insect cells was used to study the catalytical activity to imipramine metabolism and stereoselective metabolism of propranolol. The metabolites of imipramine were identified of hydroxyl imipramine and desipramine by LC-MS/MS. There are some differences between CYP2D6.1 and CYP2D6.10 activity. The kinetics parameters K m, V max, and CL int are 11.77 ± 0.91 μmol/L, 0.4235 ± 0.05 nmol/nmol CYP2D6.1/min and 3.60 × 10 -5 ml/min/nmol CYP2D6.1 (n = 3) for CYP2D6.1, respectively, and 9.05 ± 0.87 μmol/L, 0.42 ± 0.03 nmol/nmol CYP2D6.10/min, and 4.60 × 10 -5 ml/min/nmol CYP2D6.10 (n = 3) for CYP2D6.10. For propranolol, two metabolites were identified to be hydroxyl and N-desisopropylation propranolol by LC-MS/MS. When the substrate concentration was 0.20 μmol/L, CYP2D6.1 and CYP2D6.10 exhibited significant stereoseletivity. Furthermore, enantioselective formation has been detected. Both of CYP2D6.1 and CYP2D6.10 produced more hydroxyl propranolol from the R-(+)-isomer than from the S-(-)-isomer while there was no obvious difference for N-desisopropylation propranolol production between R-(+)- and S-(-)- isomer. In summary, there is a somewhat different catalytical activity and stereoselectivity between the human recombinant CYP2D6.1 and CYP2D6.10. The data we got will be helpful in preclinical research and clinical use of CYP2D6 substrates.