识别和描述的细胞色素P450酶参与N-dealkylation普罗帕酮的分子基础交互潜在的活性代谢物和可变的性格。

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Botsch年代,Gautier JC,博纳P, Eichelbaum M,获得香港

识别和描述的细胞色素P450酶参与N-dealkylation普罗帕酮的分子基础交互潜在的活性代谢物和可变的性格。

摩尔杂志。1993年1月,43 (1):120 - 6。

PubMed ID

8423765 (在PubMed

]

文摘

代谢酶的活性决定了等离子体浓度,因此药物的影响。识别这些酶可能允许的预测药物的相互作用潜力和变化产生一定的途径。抗心律失常的心律平广泛biotransformed活性代谢物5-hydroxypropafenone N-desalkylpropafenone。而5-hydroxylation CYP2D6酶催化,酶参与N-dealkylation尚未确定。因此,我们为所涉及的酶的形成N-desalkylpropafenone通过使用体外(人类肝脏微粒体、特定的抗体或抑制剂和稳定表达的细胞色素P450酶(P450)]和体内(形成N-desalkylpropafenone患者长期治疗的条件下)的方法。形成N-desalkylpropafenone可以由Michaelis-Menten动力学描述。很强的相关性之间观察到的最大速度形成的Vmax N-desalkylpropafenone和CYP1A2 (r = 0.83, p < 0.001)和CYP3A (r = 0.54, p < 0.05)在20人类肝脏微粒体的一部分。体外内在许可(来自Vmax /公里)表示个人间变异性在七个人类肝脏(从0.01到0.1毫升/人力资源/毫克的蛋白质)。抗体针对CYP3A和CYP1A2抑制形成N-desalkylpropafenone 54 + / - 10%和24 + / - 16%,分别。CYP2D6-mediated 5-hydroxypropafenone的形成是受到这些抗体的影响。 Verapamil (substrate of CYP3A4 and CYP1A2) and midazolam (substrate of CYP3A4) were competitive inhibitors of N-desalkylpropafenone formation (Ki = 70 microM and 25 microM for verapamil and midazolam, respectively). Coding sequences for CYP1A2 and CYP3A4 were inserted in a yeast expression vector and introduced into Saccharomyces cerevisiae strain W(R). Both CYP1A2 and CYP3A4 catalyzed N-dealkylation of propafenone, with specific activities of 0.32 pmol/min/pmol of P450 and 0.16 pmol/min/pmol of P450, respectively. Our data indicate that N-dealkylation of propafenone is mediated via CYP3A4 and CYP1A2. From experiments on the molecular level interactions of propafenone with other drugs that are metabolized by CYP3A4 and CYP1A2 can be predicted. Such interactions have been reported for cyclosporin, rifampicin, warfarin, and theophylline. Moreover, in vitro intrinsic clearances showed a wide interindividual variability. Therefore, variable plasma concentrations of the active metabolite N-desalkylpropafenone are expected in vivo. We tested this hypothesis in 14 patients (dose of 150 mg of propafenone three times per day) during chronic oral therapy and observed steady state plasma concentrations of N-desalkylpropafenone ranging from 4 to 293 ng/ml.(ABSTRACT TRUNCATED AT 400 WORDS)

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药物酶

药物	酶	类	生物	药理作用	行动
奥美拉唑	细胞色素P450 3 a4	蛋白质	人类	未知的	底物 抑制剂 诱导物	细节
普罗帕酮	细胞色素P450 1 a2	蛋白质	人类	未知的	底物 抑制剂	细节
普罗帕酮	细胞色素P450 2 d6	蛋白质	人类	未知的	底物 抑制剂	细节