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: 7881622
• 负责人: Aiming Yu
• 金额: $ 34.18万
• 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/7881622
• 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）：拟议工作的总体目标是描述吲哚烷基胺（IAA）代谢和药物相互作用的药物遗传学。 IAA 异生物质是一类已被广泛滥用的主要精神活性药物。目前，这些物质很容易在秘密实验室合成并通过互联网出售。过量服用或同时使用 IAA 异生素可能会导致严重甚至致命的“血清素中毒”。 IAA 药物的药理和毒理作用表现出广泛的个体差异，但潜在的机制仍然难以捉摸。 IAA 代谢和处置的变化可能是原因之一。最近，我们发现 O-去甲基化是五种 IAA 药物的重要代谢途径。以其遗传多态性而闻名的细胞色素 P450 2D6 (CYP2D6) 介导此反应。因此，我们假设CYP2D6多态性可能是个体间对IAA反应的重要决定因素，并且这种现象将在IAA代谢、药代动力学和药效学以及IAA药物相互作用的严重性方面产生相当大的变异性。在目标#1中，建议对基因型肝细胞进行动力学研究，以评估 IAA 内在清除率和代谢物产生与 CYP2D6 基因型或表型相关的变异性。目标 #2 将检验 IAA 药物作用的变化与 CYP2D6 状态相关的假设。我们建议使用 CYP2D6 转基因小鼠模型进行这些研究，这将使我们能够在系统水平上直接评估 CYP2D6 对 IAA 代谢、药代动力学和动力学的影响。目标 #3 将研究 IAA 药物间相互作用，这种相互作用被认为发生在药效学和药代动力学水平上。我们将采用相同的小鼠模型来表征它们与 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终点来评估 IAA 药物遗传学和复杂的药物相互作用。根据我们有趣的初步数据，我们相信拟议的工作将增进对 IAA 药理学和毒理学的理解。控制 IAA 动力学和药物对动物行为、脑神经递质和体温影响的遗传因素的表征预计将提供有关 IAA 代谢和毒理学决定因素的重要基本信息和见解。