Exogenous and Endogenous Biomarkers of CYP2D6 Variability in Pediatrics

说明(申请人提供)：细胞色素P450 2D6(细胞色素P450 2D6)参与约25%的临床用药的代谢，其中几种药物常用于不同年龄段的儿童。与该基因的“正常”版本相比，该基因有几种变异形式，与没有活性或活性降低有关。虽然对CYP2D6的基因检测变得越来越容易，但仅用遗传信息指导儿童药物治疗可能是不够的，因为基因-表型关系可能会受到出生到青春期之间发生的发育变化的影响。这项建议的目的是调查个体发育和遗传变异在学龄儿童和青少年中观察到的CYP2D6活性变异中的相对作用，并评估观察到的变异的功能后果。为了实现这些目标，总共180名6至15岁的儿童和青少年，包括60名被初步诊断为注意力缺陷多动障碍(ADHD)的患者和120名年龄和性别匹配的对照组，将在3年内每6个月测量一次他们的CYP2D6活性(目标1)。活性测量将利用非处方止咳药右美沙芬或“DM”，这是一种确定CYP2D6表型的标准探针。这一过程包括注射0.5毫克/公斤的DM，并在接下来的四个小时内收集尿液。根据尿样中存在的DM和由CYP2D6产生的代谢物右旋沙芬(DX)的相对量来指定CYP2D6的活性或“代谢物”状态。Aim 2将根据为Aim 1收集的尿样中存在的代谢组生物标记物模式来测试这一假设，即根据为Aim 1收集的尿样中存在的代谢组生物标志物模式，可以将CYP2D6代谢不良者与广泛代谢者区分开来。在Aim 3的研究中，将使用的DM将包含稳定的碳同位素([13C])，以确定快速、基于办公室的对CYP2D6的评估是否可行。这项测试的原理是，在呼出的空气中，由CYP2D6介导的[13C]-右美沙芬O-去甲基化释放的[13C]-甲基以[13C]O2的形式出现，称为呼气测试。最后，将通过比较两组ADHD广泛代谢物中非刺激性药物托莫西汀(Strattera(R))的全身暴露情况来评估CYP2D6活性(目标4)的功能后果，这些代谢物来自呼气测试数据分布的最高和最低20%。最终，这项研究的目标是通过为个别患者选择适当剂量的正确药物，使儿童的药物使用个性化。

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.