Exogenous and Endogenous Biomarkers of CYP2D6 Variability in Pediatrics

描述（由申请人提供）：细胞色素P450 2D6 （CYP2D6）参与临床使用的约25%的药物的代谢，其中几种通常用于不同年龄的儿童。CYP2D6基因有几种变体形式，与“正常”版本的基因相比，这些变体形式与无活性或活性降低有关。虽然CYP2D6的基因检测越来越容易获得，但仅凭遗传信息指导药物治疗可能不足以治疗儿童，因为基因型-表型关系可能受到出生和青春期之间发生的发育变化的影响。本提案的目的是研究个体发育和遗传变异在学龄儿童和青少年中观察到的CYP2D6活性变异性中的相对作用，并评估观察到的变异性的功能后果。为了实现这些目标，共有180名6至15岁的儿童和青少年，包括主要诊断为注意缺陷多动障碍（ADHD, n=60）和年龄和性别匹配的对照组（n=120），将每6个月测量一次CYP2D6活性，持续3年（目的1）。活性测量将利用非处方止咳药右美沙芬或“DM”，这是测定CYP2D6表型的标准探针。该过程包括给予0.5 mg/kg剂量的DM，并在接下来的4小时内收集尿液。CYP2D6活性或“代谢物”状态是根据尿样中DM和CYP2D6产生的代谢物dextrorphan （DX）的相对量来确定的。Aim 2将根据Aim 1收集的尿液样本中存在的代谢组学生物标志物模式，验证CYP2D6代谢不良者可以与广泛代谢者区分的假设。在Aim 3的研究中，将使用的DM将含有稳定的碳同位素（[13C]），以确定快速、基于办公室的CYP2D6评估是否可行。该测试的原理是cyp2d6介导的[13C]-右美沙芬o -去甲基化释放的[13C]-甲基在呼气中以[13C]O2的形式出现，称为“呼吸测试”。最后，CYP2D6活性的功能后果（Aim 4）将通过比较两组ADHD广泛代谢物的全身暴露于非兴奋剂药物阿托西汀（Strattera(R)）来评估，这些代谢物来自呼吸测试数据分布的最高和最低的20百分位数。最终，这项研究的目标是通过为个体患者选择适当剂量的正确药物来个性化儿童药物的使用。

DESCRIPTION (provided by applicant): Cytochrome P450 2D6 (CYP2D6) is involved in the metabolism of approximately 25% of drugs used clinically several of which are commonly used in children of various ages. The CYP2D6 gene has several variant forms that are associated with no activity or reduced activity compared to the "normal" version of the gene. While genetic testing for CYP2D6 is becoming more accessible, guiding drug therapy with genetic information alone may not be sufficient in children as the genotype-phenotype relationship may be influenced by developmental changes that occur between birth and adolescence. The purpose of this proposal is to investigate the relative roles of ontogeny and genetic variation in the observed variability in CYP2D6 activity in school- aged children and adolescents, and to assess the functional consequences of the observed variability. To achieve these goals, a total of 180 children and adolescents from 6 to 15 years of age, consisting of patients with a primary diagnosis of attention deficit-hyperactivity disorder (ADHD; n=60) and age- and sex-matched controls (n=120), will have their CYP2D6 activity measured every 6 months for 3 years (Aim 1). The activity measurement will utilize the over- the-counter cough suppressant, dextromethorphan or "DM", a standard probe for determining CYP2D6 phenotype. The procedure involves administering a 0.5 mg/kg dose of DM and collecting urine over the following four hours. CYP2D6 activity or "metabolizer" status is assigned based on the relative amounts of DM and the metabolite produced by CYP2D6, dextrorphan (DX), present in the urine sample. Aim 2 will test the hypothesis that CYP2D6 poor metabolizers can be distinguished from extensive metabolizers based on a metabolomic biomarker pattern present in urine samples collected for Aim 1. In the study for Aim 3, the DM to be used will contain a stable isotope of carbon ([13C]) to determine if a rapid, office-based assessment of CYP2D6 is feasible. The principle of this test is that the [13C]-methyl group released by CYP2D6-mediated O-demethylation of [13C]-dextromethorphan appears in expired air as [13C]O2, referred to as a 'breath test'. Finally, the functional consequences of CYP2D6 activity (Aim 4) will be assessed by comparing the systemic exposure to the non-stimulant drug atomoxetine (Strattera(R)) in two groups of ADHD extensive metabolizers drawn from the highest and lowest 20th percentiles of the breath test data distribution. Ultimately, the goal of the research is to personalize the use of medications in children by selecting the appropriate dose of the correct medication for individual patients. PUBLIC HEALTH RELEVANCE: Cytochrome P450 2D6 (CYP2D6) is an important enzyme in the body for breaking down many medications that are commonly used in children of various ages. The purpose of this proposal is to investigate the relative roles of development and genetic variation in CYP2D6 activity in school-aged children and adolescents using the over-the-counter cough suppressant, dextromethorphan or "DM", a standard probe for determining CYP2D6 phenotype. Embedded in the study design are sub-studies to investigate the potential of a DM breath test to serve as a rapid test of CYP2D6 activity that may be performed in doctors' offices as well as a search for normal body by-products that reflect differences in enzyme activity. Ultimately, the goal of the research is to personalize the use of medications in children by selecting the appropriate dose of the correct medication for individual patients.