CYP2D6*10基因型对托特罗定药代动力学的影响。

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大石，千叶，马霍特拉，苏瓦

CYP2D6*10基因型对托特罗定药代动力学的影响。

《药物代谢杂志》2010年9月38日(9):1456-63。doi: 10.1124 / dmd.110.033407。Epub 2010 6月7日。

PubMed ID

20530222 (PubMed视图

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摘要

本研究旨在研究CYP2D6*10的功能降低等位基因对托特罗定药代动力学的影响，该等位基因可能是中间代谢物(IM)的原因。托特罗定主要由CYP2D6代谢为活性5-羟甲基代谢物(5-HM)， 5-HM也由CYP2D6代谢。亚裔和白人健康志愿者(n = 108)每天接受一次多剂量托特罗定，并测量托特罗定和5-HM的血清浓度。所有受试者均进行CYP2D6基因分型。托特罗定暴露[曲线下面积(AUC)]增加的顺序为CYP2D6*1/*1[广泛的代谢物(EM)] < CYP2D6*1/*10 < CYP2D6*10/*10 < CYP2D6*5/*10。预计5-HM曝光的顺序会颠倒。然而，5-HM AUC的增加顺序与托特罗定相同。这一现象可以通过考虑CYP2D6同时介导5-HM的产生和消除来解释。CYP2D6*10/*10中托特罗定和5-HM暴露均高于CYP2D6*1/*1(分别为3倍和1.5倍)。CYP2D6*4/*4 [poor metabolizer (PM)]未产生5-HM，托特罗定暴露量比CYP2D6*1/*1高20倍。 With consideration for higher protein binding of tolterodine than 5-HM, the exposure as a sum of the unbound fraction of tolterodine and 5-HM (active moiety) in CYP2D6*10/*10 was 1.8-fold higher than that in CYP2D6*1/*1 and was also higher than that in CYP2D6*4/*4. Simulation using the values of EM and PM demonstrated that the maximum possible active moiety exposure was around the observed values of CYP2D6*5/*10, which were 1.9-fold higher than those for CYP2D6*1/*1. This is the first report to provide an example in which the IM shows higher exposure to pharmacological active moiety than the EM and PM.

引用本文的药物库数据

药物酶

药物	酶	种类	生物	药理作用	行动
Tolterodine	细胞色素P450 2D6	蛋白质	人类	未知的	底物	细节