Pharmacogenetics in indolealkylamine metabolism and drug interactions

描述（由申请方提供）：拟定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外源性物质是一类被广泛滥用的精神活性药物。目前，这些物质很容易在秘密实验室合成，并通过互联网销售。过量或同时使用IAA外源性物质可能会导致严重甚至致命的“5-羟色胺毒性”。IAA药物的药理学和毒理学作用表现出广泛的个体差异，但其潜在的机制仍然难以捉摸。IAA代谢和分配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。细胞色素P450 2D6（CYP 2D6），这是已知的遗传多态性，介导这一反应。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程度方面产生相当大的变异性。在目标#1中，建议采用基因型肝细胞进行动力学研究，以评估IAA固有清除率和代谢产物产生与CYP2D6基因型或表型相关的变异性。目的#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，这将使我们能够直接评估CYP2D6对IAA代谢，药代动力学和动力学在全身水平的影响。目标#3将研究IAA药物-药物相互作用，这在药效学和药代动力学水平上都有理由发生。我们将采用相同的小鼠模型来表征它们与CYP2D6状态和IAA剂量组合的相关性。我们将使用动力学，生化，生理和行为测量作为终点，以评估IAA药物遗传学和复杂的药物相互作用。基于我们有趣的初步数据，我们相信，拟议的工作将促进对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，脑神经递质和体温的影响的遗传因素的表征，预计提供重要的基本信息和见解有关IAA代谢和毒理学决定因素。

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.