Pharmacogenetics of Methadone

描述(逐字摘自申请者摘要)：美沙酮被用作 阿片类药物成瘾的维持治疗，是 妊娠期阿片成瘾妇女的处理。孕期美沙酮剂量 分娩与新生儿戒断的严重程度密切相关。因此， 美沙酮剂量是决定产妇健康和分娩的关键因素。 结果。美沙酮的大多数给药方案是经验性的滴定剂量 针对戒断症状，并在适当的情况下，关于阿片类药物的病史 使用。尽管美沙酮已经使用了近50年，但其细节 令人惊讶的是，药物动力学并不完整。线性关系一直是 美沙酮剂量与血药浓度之间的关系 只解释了不到50%的可变性。美沙酮被作为一种 称为(R)-美沙酮和(S)-美沙酮的两种对映体的混合物(50：50)，但 (R)美沙酮几乎占了外消旋剂量的所有阿片类药物的作用。 美沙酮的处置似乎是立体选择性的和遗传的。 和环境控制。美沙酮的药物遗传学贡献 性情方面的研究很少。因此，一个为期三年的双站点， 建议进行协作ROL研究，以确定主要的药物遗传学 影响美沙酮在女性体内倾向的变量。少校 需要研究的决定因素包括1)性别，2)民族血统 (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 α1-酸性糖蛋白(AGP)的表型，5)皮质醇比率 细胞色素P-450(CYP)3A4活性的替代标记，以及6) 细胞色素P450 2D6。将对美沙酮的处置进行严格的药代动力学研究 在健康的志愿者女性中完成，并将结果与健康的男性进行比较。 将寻求美沙酮的药代动力学之间的相关性 在我们的初步数据中显示的对映体和影响措施很高 相关(瞳孔收缩、口温、血糖 浓度)。人口统计学和药代动力学数据将从600 接受美沙酮治疗的女性(查尔斯顿240人，辛辛那提360人) 维修。将构建一个群体药代动力学模型并进行测试 预测活性(R)-美沙酮在治疗前后的血药浓度 怀孕了。这项研究的目标是描述主要的药物遗传学 影响女性体内美沙酮浓度的因素，并通过 药代动力学分析，以形成更清晰的认识 特定人群美沙酮的剂量-剂量-效应关系 风险，怀孕的鸦片成瘾的女人。这项研究将构成以下内容的基础 后续研究应该为给药提供更合理的基础 孕期吸毒者中的美沙酮。

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.