Pharmacogenetics of Methadone

描述（来自申请人摘要的逐字）：美沙酮用作 维持治疗阿片类药物成瘾，是标准的护理， 对鸦片成瘾孕妇的管理母亲美沙酮剂量 分娩与新生儿戒断的严重程度密切相关。因此，在本发明中， 美沙酮剂量是决定产妇健康和分娩的关键因素 结果。美沙酮的大多数剂量方案是经验性的，滴定剂量 针对戒断症状，并在适当情况下，对阿片类药物的历史 使用.尽管使用美沙酮近50年，其细节 药代动力学令人惊讶地不完整。线性关系一直是 报告了美沙酮剂量和血浆药物浓度之间的关系，但药物剂量 解释了不到50%的变异美沙酮是一种 2种对映体的混合物（50：50），称为（R）-美沙酮和（S）-美沙酮，但 （R）美沙酮几乎占了外消旋剂量的所有阿片样物质作用。 美沙酮的处置似乎是立体选择性的， 和环境控制。药物遗传学对美沙酮 性格得到很少的研究。因此，一个为期三年的双站点， 提出了一项合作RO 1研究，以确定主要的药物遗传学 影响美沙酮在女性中分布的变量。主要 研究的决定因素包括：1）性别，2）种族 （非洲裔美国人与高加索人背景），3）对映体选择性代谢; 4)美沙酮对映体的血浆蛋白结合，5）遗传决定 α 1-酸性糖蛋白（AGP）的表型，5）皮质醇比率作为 细胞色素P-450（CYP）3A 4活性替代标记物，和6） CYP2D6。一项严格的美沙酮处置药代动力学研究将在 在健康女性志愿者中完成，并将结果与健康男性进行比较。 将寻求美沙酮的药代动力学与 对映异构体和效果的措施表明，在我们的初步数据是高度 相关（瞳孔收缩、口腔温度、血糖 浓度）。将从600名受试者中获得人口统计学和药代动力学数据 接受美沙酮的妇女（查尔斯顿240人，辛辛那提360人） 上维护将构建并检验群体药代动力学模型 预测活性（R）-美沙酮的血浆浓度之前和期间 怀孕这项研究的目的是描述主要的药物遗传学 影响妇女美沙酮浓度的因素，以及通过 药代动力学分析，以更清楚地了解 美沙酮在特殊人群中的剂量-浓度-效应关系 风险，怀孕的鸦片成瘾的女人。这项研究将为以下方面奠定基础： 后续研究应提供更合理的给药依据 美沙酮在怀孕成瘾者。

DESCRIPTION (Verbatim from the Applicant's Abstract): Methadone is used as a maintenance treatment for opiate addiction and is the standard of care in the management of the pregnant opiate-addicted woman. Maternal methadone dose at delivery and the severity of neonatal withdrawal are closely related. Thus, methadone dose is a critical factor determining both maternal health and birth outcome. Most dosage regimens for methadone are empirical, titrating dose against withdrawal symptoms and, where appropriate, on the history of opiate use. Despite the use of methadone for nearly 50 years, details of its pharmacokinetics are surprisingly incomplete. A linear relationship has been reported between methadone dose and drug concentration in plasma but drug dose explains less than 50 percent of the variability. Methadone is marketed as a mixture (50:50) of 2 enantiomers called (R)-methadone and (S)-methadone, but (R)methadone accounts for nearly all of the opioid effects of the racemic dose. The disposition of methadone appears to be stereoselective and under genetic and environmental control. The pharmacogenetic contribution to methadone's disposition has received little study. Accordingly, a three-year dual-site, collaborative ROl study is proposed to define the major pharmacogenetic variables that influence the disposition of methadone in women. The major determinants to be studied include 1) gender, 2) ethnic origin (Africian-American vs. Caucasian background), 3) enantioselective metabolism; 4) plasma protein binding of methadone's enantiomers, 5) genetically determined phenotype of alpha1-acid glycoprotein (AGP), 5) the cortisol ratio as a surrogate marker of cytochrome P-450 (CYP) 3A4 activity, and 6) genotype of CYP2D6. A rigorous pharmacokinetic study of methadone disposition will be completed in healthy volunteer women and the results compared to healthy men. Correlations will be sought between the pharmacokinetics of methadone's enantiomers and effect measures shown in our preliminary data to be highly related (pupillary constriction, oral temperature, blood glucose concentration). Demographic and pharmacokinetic data will be obtained from 600 women (240 in Charleston and 360 in Cincinnati) receiving methadone maintenance. A population pharmacokinetic model will be constructed and tested to predict plasma concentrations of active (R)-methadone before and during pregnancy. The goals of this research are to describe the major pharmacogenetic factors which influence methadone concentration in women, and through pharmacokinetic analyses, to form a clearer understanding of the dose-concentration-effect relationship of methadone in a special population at risk, the pregnant opiate-addicted woman. This study will form the basis for subsequent studies which should provide a more rational basis for dosing of methadone in pregnant addicts.