Comparison of cytochrome p450 mediated metabolism of three central nervous system acting drugs.
Comparison of cytochrome p450 mediated metabolism of three central nervous system acting drugs.
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细胞色素p450介导的三种中枢神经系统作用药物代谢的比较。
DOI：
10.1248/cpb.c12-00719
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发表时间：
2012
影响因子：
1.7
通讯作者：
T. Uno
中科院分区：
文献类型：
--
作者：
Tamer Z. Attia;Taku Yamashita;Masayoshi Miyamoto;A. Koizumi;Y. Yasuhara;J. Node;Y. Erikawa;Y. Komiyama;C. Horii;Mayu Yamada;Mahmoud A Omar;O. Abdelmageed;S. M. Derayea;T. Uno
通过测定酶动力学参数、米氏常数（K（m））、最大反应速度（V（max））和固有清除率（CL（int））来研究细胞色素P450（CYP）介导的代谢反应是药物发现和开发的重要方面。动力学参数可用于预测人体给药前的清除率，并更好地了解体内清除机制。在这项研究中，研究了三种主要的肝纤维化亚型（2C19、2D6和3A4）对结构不同的中枢神经系统（CNS）作用药物阿米替林、氟奋乃静和多硫平的代谢活性。通过使用我们的新的体外评价系统，我们可以比较动力学参数的代谢氟奋乃静和dothiepin的第一次。比较由此获得的CL（int）值，我们得出结论，2C19可能是三环类抗抑郁药的主要代谢活性，如预期，但不是吩噻嗪相关抗精神病药物。由于中枢神经系统药物的代谢易受人类基因单核苷酸多态性的影响，我们的研究结果表明，吩噻嗪可能是中枢神经系统药物临床应用的替代品。
The investigation of cytochrome P450 (CYP) mediated metabolism reactions by determination of enzyme kinetic parameters, Michaelis constant (K(m)), maximum reaction velocity (V(max)), and intrinsic clearance (CL(int)) is important aspects in discovery and development of drugs. The kinetic parameters can be used to predict the clearance prior to human administration and for better understanding the mechanism of clearance in vivo. In this study, the metabolic activities of three major hepatic CYP isoforms (2C19, 2D6, and 3A4) were investigated on structurally different central nervous system (CNS) acting drugs, amitriptyline, fluphenazine, and dothiepin. By using our novel in vitro evaluation system, we could compare the kinetic parameters for the metabolism of fluphenazine and dothiepin for the first time. Comparing CL(int) values thus obtained, we concluded that 2C19 could be predominant for metabolic activity on tricyclic antidepressants as expected, but not on phenothiazine-related antipsychotic drugs. Since the metabolism of CNS drugs is susceptible to single nucleotide polymorphisms of human gene, our results suggest that phenothiazine could be an alternative to clinical application of CNS drugs.
DOI：
--
发表时间：
1999-09
期刊：
Drug metabolism and disposition: the biological fate of chemicals
影响因子：
--
作者：
Jae-Gook Shin;N. Soukhova;D. Flockhart
通讯作者：
Jae-Gook Shin;N. Soukhova;D. Flockhart
抗抑郁药米氮平的体外代谢：细胞色素 P-450 1A2、2D6 和 3A4 的贡献。
DOI：
--
发表时间：
2000
期刊：
Drug metabolism and disposition: the biological fate of chemicals
影响因子：
--
作者：
Störmer,E;vonMoltke,LL;Shader,RI;Greenblatt,DJ
通讯作者：
Greenblatt,DJ