Exogenous and Endogenous Biomarkers of CYP2D6 Variability in Pediatrics

儿科 CYP2D6 变异的外源性和内源性生物标志物

• 批准号: 8249003
• 负责人: JAMES STEVEN LEEDER
• 金额: $ 54.2万
• 依托单位: CHILDREN'S MERCY HOSP (KANSAS CITY, MO)
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-04-01 至 2015-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8249003
• 关键词: 15 year old; 2 year old; Address; Adolescence; Adolescent; Adverse reactions; Age; Air; Alleles; Analgesics; Attention deficit hyperactivity disorder; Behavioral; Biological Markers; Birth; Breath Tests; Carbon; Child; Childhood; Codeine; Coughing; Cytochrome P-450 CYP2D6; Data; Development; Dextromethorphan; Dextrorphan; Diagnosis; Dose; Drug usage; Environmental Risk Factor; Enzymes; Exposure to; Fluoxetine; Gene Dosage; Genes; Genetic; Genetic Variation; Genetic screening method; Genotype; Goals; Growth; Growth and Development function; Hour; Human Genome Project; Individual; International; Investments; Lead; Life; Link; Measurement; Measures; Mediating; Metabolic Biotransformation; Metabolism; Neonatal; Paroxetine; Patients; Pattern; Pediatrics; Pharmaceutical Preparations; Pharmacogenetics; Pharmacotherapy; Phenotype; Procedures; Promethazine; Proteins; Prozac; Relative (related person); Research; Research Design; Resolution; Risk; Role; Sampling; School-Age Population; Selective Serotonin Reuptake Inhibitor; Self-Injurious Behavior; Strattera; Syndrome; Testing; Third Pregnancy Trimester; Time; Toxic effect; Translating; Treatment Failure; United States Food and Drug Administration; Urine; Variant; Ventilatory Depression; atomoxetine; base; demethylation; drug clearance; enzyme activity; inhibitor/antagonist; knowledge translation; metabolomics; methyl group; paxil; public health relevance; sex; stable isotope; urinary

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.

描述（由申请人提供）：细胞色素P450 2D6（CYP2D6）参与了大约25％使用的药物的代谢，其中几种通常用于不同年龄的儿童。与基因的“正常”版本相比，CYP2D6基因具有几种与无活性或活性减少相关的变体形式。虽然CYP2D6的基因检测变得越来越容易获得，但仅使用遗传信息的指导药物治疗可能不足以在儿童中足够，因为基因型 - 表型关系可能受到出生和青少年之间发生的发展变化的影响。该提案的目的是研究校学生和青少年在CYP2D6活性中观察到的变异性中的个体发育和遗传变异的相对作用，并评估观察到的变异性的功能后果。为了实现这些目标，总共有180名6至15岁的儿童和青少年，包括对注意力不足 - 疾病的主要诊断（ADHD； n = 60）和年龄和性别匹配的对照（n = 120）的患者，将每6个月测量3年的CYP2D6活动（AIM 1）。活性测量将利用过度抑制剂抑制剂，右美甲泛或“ DM”，这是确定CYP2D6表型的标准探针。该过程涉及在接下来的四个小时内给予0.5 mg/kg剂量的DM并收集尿液。 CYP2D6活性或“代谢剂”状态是基于尿液样品中存在的CYP2D6，右旋芬（DX）产生的DM的相对量和代谢物的相对量分配的。 AIM 2将检验以下假设：CYP2D6可以根据AIM 1收集的尿液样本中存在的代谢组生物标志物模式与广泛的代谢剂区分开。在目标3的研究中，要使用的DM在研究中，使用的DM将包含一个稳定的碳（[13C]），以确定cappy in Is Is Is IS CEP2 IS CYP2 IS of cyp2 ins CYP2 f sep2。该测试的原理是，[13C] - 二甲状腺甲基释放的[13C] - 甲基基团在过期的空气中以[13C] O2的形式出现，称为“呼气测试”。最后，将通过将两组ADHD广泛的代谢器中的非刺激药物原子苷（Strattera（r））进行比较，将评估CYP2D6活性（AIM 4）的功能后果（AIM 4）。最终，该研究的目的是通过选择适合个别患者的正确剂量的儿童使用药物使用。 公共卫生相关性：细胞色素P450 2D6（CYP2D6）是体内重要的酶，用于分解许多在各个年龄段儿童中常用的许多药物。该提案的目的是研究使用非处方咳嗽抑制剂，右美甲芬或“ DM”的学龄儿童和青少年中CYP2D6活性中的发育和遗传变异的相对作用，这是确定CYP2D6表型的标准探针。研究设计中嵌入的是子研究，以研究DM呼气测试的潜力，以作为CYP2D6活性的快速测试，该测试可能在医生的办公室中进行，并寻找反映酶活性差异的正常身体副产品。最终，该研究的目的是通过选择适合个别患者的正确剂量的儿童使用药物使用。