Pharmacogenetics in indolealkylamine metabolism and drug interactions

吲哚烷基胺代谢和药物相互作用的药物遗传学

• 批准号: 7664305
• 负责人: Aiming Yu
• 金额: $ 34.52万
• 依托单位: STATE UNIVERSITY OF NEW YORK AT BUFFALO
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-08-01 至 2012-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7664305
• 关键词: Affinity; Animal Behavior; Animals; Behavior Control; Behavioral; Biochemical; Body Temperature; Brain; Carbolines; Complex; Cytochrome P-450 CYP2D6; Cytochrome P450; Data; Deamination; Designer Drugs; Dose; Drug Interactions; Drug Kinetics; Enzymes; Exhibits; Foundations; Future; Genetic; Genetic Determinism; Genetic Polymorphism; Genetic Variation; Genotype; Hallucinogens; Harmaline; Hepatocyte; Human; In Vitro; Individual; Internet; Intoxication; Investigation; Kinetics; Laboratories; Mediating; Metabolic; Metabolic Pathway; Metabolism; Modality; Monoamine Oxidase; Monoamine Oxidase A; Monoamine Oxidase Inhibitors; Mus; N,N-Dimethyltryptamine; Nature; Neurotransmitters; Overdose; Pharmaceutical Preparations; Pharmacodynamics; Pharmacogenetics; Pharmacology and Toxicology; Phenotype; Physiological; Play; Production; Property; Psychotropic Drugs; Reaction; Research Personnel; Risk; Role; Schedule; Serotonin; Serotonin Agents; Serotonin Receptor 5-HT2A; Serotonin Syndrome; Severities; Shunt Device; Stimulus; Students; Surveys; Testing; Toxic effect; Transgenic Organisms; United States; Variant; Work; Xenobiotics; base; behavior measurement; demethylation; drug metabolism; ecstasy; harmaline abuse; high school; in vivo Model; insight; monoamine; mouse model; next generation; programs; response; serotonin receptor

DESCRIPTION (provided by applicant): The overall objective of the proposed work is to delineate the pharmacogenetics of indolealkylamine (IAA) metabolism and drug-drug interactions. IAA xenobiotics represent a major class of psychoactive drugs that have seen widespread abuse. Currently, these substances are easily synthesized in clandestine laboratories and sold via the internet. Overdosing or concomitant use of IAA xenobiotics may cause severe or even fatal "serotonin toxicity". The pharmacological and toxicological effects of IAA drugs exhibit broad interindividual variations, but the underlying mechanisms remain elusive. Variation of IAA metabolism and disposition is likely one reason. Recently, we have shown that O-demethylation is a significant metabolic pathway for five IAA drugs. Cytochrome P450 2D6 (CYP2D6), which is known for its genetic polymorphism, mediates this reaction. We therefore hypothesize that CYP2D6 polymorphism may be an important determinant of the inter-individual responses toward IAA, and that this phenomenon will produce considerable variability in IAA metabolism, pharmacokinetics and pharmacodynamics, as well as the severity of IAA drug-drug interactions. In Aim #1, kinetic studies with genotyped hepatocytes are proposed to assess the variability of IAA intrinsic clearance and metabolite production in relation to CYP2D6 genotypes or phenotypes. Aim #2 will test the hypothesis that variations of IAA drug effects are related to CYP2D6 status. We propose to use the CYP2D6-trangenic mouse model for these studies, which will allow us to assess directly the impact of CYP2D6 on IAA metabolism, pharmacokinetics, and dynamics at the systemic level. Aim #3 will investigate IAA drug-drug interactions, which is reasoned to occur at both the pharmacodynamic and pharmacokinetic levels. We will employ the same mouse models to characterize their association with CYP2D6 status and IAA dose combinations. We will use kinetic, biochemical, physiological, and behavioral measurements as endpoints to assess IAA pharmacogenetics and complex drug-drug interactions. Based upon our intriguing preliminary data, we believe that the proposed work will advance the understanding of IAA pharmacology and toxicology. Characterization of the genetic factors that control IAA kinetics and drug effects on animal behavior, brain neurotransmitters, and body temperature is anticipated to provide important basic information and insights concerning IAA metabolic and toxicological determinants.

描述（由申请人提供）：拟议工作的总体目的是描述吲哚金胺（IAA）代谢和药物毒用相互作用的药物遗传学。 IAA异生元代表了大量的精神活性药物，这些药物已经广泛滥用。目前，这些物质很容易在秘密实验室中合成并通过互联网出售。过量或同时使用IAA异种生物可能会导致严重甚至致命的“ 5-羟色胺毒性”。 IAA药物的药理和毒理学作用表现出广泛的个体变化，但潜在的机制仍然难以捉摸。 IAA代谢和性格的变化可能是原因之一。最近，我们表明O-二甲基化是五种IAA药物的重要代谢途径。细胞色素P450 2d6（CYP2D6）以其遗传多态性而闻名，它介导了这种反应。因此，我们假设CYP2D6多态性可能是对IAA的个体反应的重要决定因素，并且这种现象将导致IAA代谢，药代动力学和药物动力学以及IAA药物互动相互作用的严重性。在AIM＃1中，提出了具有基因分型肝细胞的动力学研究来评估与CYP2D6基因型或表型相关的IAA内在清除率和代谢物产生的变异性。 AIM＃2将检验以下假设：IAA药物效应的变化与CYP2D6状态有关。我们建议将CYP2D6-跨然小鼠模型用于这些研究，这将使我们能够直接评估CYP2D6对系统水平上IAA代谢，药代动力学和动力学的影响。 AIM＃3将研究IAA药物 - 药物相互作用，这有理由在药效和药代动力学水平上发生。我们将采用相同的鼠标模型来表征它们与CYP2D6状态和IAA剂量组合的关联。我们将使用动力学，生化，生理和行为测量作为评估IAA药物遗传学和复杂的药物相互作用的终点。根据我们有趣的初步数据，我们认为拟议的工作将提高对IAA药理学和毒理学的理解。预计控制IAA动力学和药物对动物行为，脑神经递质和体温的影响的遗传因素的表征将提供有关IAA代谢和毒理学决定因素的重要基本信息和见解。