文拉法辛的O -去甲基化和体外人工肝微粒体和从cDNA-transfected细胞微粒体:代谢抑制剂和SSRI抗抑郁药物的效果。
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Fogelman SM,施密德J, Venkatakrishnan K,冯·Moltke LL Harmatz JS,材质RI,格林布拉特DJ
文拉法辛的O -去甲基化和体外人工肝微粒体和从cDNA-transfected细胞微粒体:代谢抑制剂和SSRI抗抑郁药物的效果。
神经精神药理学。1999;20 (5):480 - 90。
- PubMed ID
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10192828 (在PubMed]
- 文摘
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文拉法辛的生物转化(VF)到它的两个主要代谢产物,O-desmethylvenlafaxine (ODV)和N-desmethylvenlafaxine (NDV)研究了体外人工肝微粒体和微粒体包含人类个体从cDNA-transfected人类lymphoblastoid细胞细胞色素。VF是coincubated选择性细胞色素P450 (CYP)抑制剂和几个选择性5 -羟色胺再摄取抑制剂(SSRIs)来评估他们的抑制作用在VF的新陈代谢。形成利率ODV孵化与人类微粒体符合Michaelis-Menten与底物抑制single-enzyme介导反应动力学。意味着参数用非线性回归:Vmax = 0.36 nmol /分钟/毫克蛋白,K (m) = 41 microM,和22901 Ks microM (Ks代表一个常数反映了底物抑制的程度)。奎尼丁(,)是一种强有力的抑制剂与Ki 0.04 microM ODV的形成,以及帕罗西汀(PX)是最有效的SSRI抑制ODV形成平均0.17 microM Ki价值。研究使用表达细胞色素表明ODV被CYP2C9形成,2 c19, 2 d6。CYP2D6 K (m),最低的是占主导地位的最高23.2 microM,内在间隙(Vmax / K (m)的比率)。没有独特的模型适用于所有四个肝脏NDV的形成考验。参数由应用single-enzyme模型Vmax = 2.14 nmol /分钟/毫克的蛋白质,和K (m) = 2504 microM。酮康唑是NDV生产的有效抑制剂,尽管其抑制活性与纯3大不如观察基质。 NDV formation was also reduced by 42% by a polyclonal rabbit antibody against rat liver CYP3A1. Studies using expressed cytochromes showed that NDV was formed by CYP2C9, -2C19, and -3A4. The highest intrinsic clearance was attributable to CYP2C19 and the lowest to CYP3A4. However the high in vivo abundance of 3A isoforms will magnify the importance of this cytochrome. Fluvoxamine (FX), at a concentration of 20 microM, decreased NDV production by 46% consistent with the capacity of FX to inhibit CYP3A, 2C9, and 2C19. These results are consistent with previous studies that show CYP2D6 and -3A4 play important roles in the formation of ODV and NDV, respectively. In addition we have shown that several other CYPs have important roles in the biotransformation of VF.
DrugBank数据引用了这篇文章
- 药物
- 药物酶
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药物 酶 类 生物 药理作用 行动 文拉法辛 细胞色素P450 2 c19 蛋白质 人类 没有底物细节 文拉法辛 细胞色素P450 2 c9 蛋白质 人类 没有底物细节 文拉法辛 细胞色素P450 2 d6 蛋白质 人类 未知的底物抑制剂细节 - 药物反应
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