Pharmacogenetics in indolealkylamine metabolism and drug interactions

描述(由申请人提供)：拟议工作的总体目标是描绘吲哚乙基胺(IAA)代谢和药物-药物相互作用的药物遗传学。IAA异生物质是一类主要的精神活性药物，已被广泛滥用。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。过量使用或同时使用IAA外源化合物可能导致严重甚至致命的“5-羟色胺中毒”。IAA药物的药理和毒理作用在个体间表现出广泛的差异，但其潜在的机制仍然难以捉摸。IAA代谢和性情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(细胞色素P450 2D6)以其遗传多态而闻名，它介导了这一反应。因此，我们假设，CYP2D6基因多态性可能是个体间对IAA反应的一个重要决定因素，这种现象将在IAA代谢、药代动力学和药效学以及IAA药物-药物相互作用的严重程度上产生相当大的变异性。在目标1中，建议对基因分型的肝细胞进行动力学研究，以评估IAA内源性清除和代谢物产生的变异性与CYP2D6基因或表型的关系。目的#2验证IAA药物效应的变化与细胞色素P4502D6基因状态有关的假设。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。目的#3将研究IAA药物与药物的相互作用，这被认为发生在药效学和药代动力学水平上。我们将使用相同的小鼠模型来表征它们与CYP2D6状态和IAA剂量组合的关系。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-药物相互作用。基于我们耐人寻味的初步数据，我们相信拟议的工作将促进对IAA药理学和毒理学的理解。对控制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有望提供关于IAA代谢和毒理学决定因素的重要基本信息和见解。

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.