PK-PD Models: The Role of Metabolites in Drug Action

PK-PD 模型：代谢物在药物作用中的作用

• 批准号: 6620734
• 负责人: HOWARD P HENDRICKSON
• 金额: $ 8.73万
• 依托单位: UNIV OF ARKANSAS FOR MED SCIS
• 依托单位国家: 美国
• 财政年份: 2002
• 资助国家: 美国
• 起止时间: 2002-05-01 至 2005-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6620734
• 关键词: biological models; blood chemistry; dextromethorphan; drug abuse; drug metabolism; drug receptors; intravenous administration; laboratory rat; liver metabolism; model design /development; oral administration; pharmacokinetics; psychopharmacology; receptor binding

The long-term goal of this Mentored Quantitative Research Career Award (K25) is to compliment the career preparation of the PI, an analytical chemist, with the training and research experience he needs to become a successful, independent researcher in drug abuse. This will be accomplished through a program of training and research in the pharmacology of drug abuse, focusing on the advanced areas of pharmacokinetics and behavioral pharmacology. In the final phase of this career development plan these diverse research areas will be integrated and used to conduct studies employing pharmacokinetic- pharmacodynamic (PK-PD) modeling. The mentor and co-mentor are both drug-abuse researchers with extensive research experience in these areas. The aims of the research-training proposal are to investigate the pharmacology of dextromethorphan with regard to its actions as a drug of abuse. Dextromethorphan, a common component of cold and cough remedies, is an increasingly abused club drug ("robo") among youth, often masquerading as more popular drugs such as MDMA ("ecstasy") or gamma-hydroxybutyrate ("GHB"). The applicant will investigate the role of dextrorphan, the primary active metabolite of dextromethorphan, as the agent responsible for the phencyclidine-like actions of dextromethorphan. Because dextromethorphan is extensively metabolized to dextrorphan in the liver, first-pass effects play a significant role in its metabolism. To test the hypothesis that oral and intravenous administration of dextromethorphan will produce unique behavioral-time profiles, dose-response and time-course studies of spontaneous locomotor activity will be studied in rats. Concurrently, serum concentration-time profiles of dextromethorphan and metabolites will be determined. PK-PD modeling of response-time and concentration-time profiles will be used to determine in vivo pharmacodynamic parameters such as, intrinsic efficacy, estimated drug-receptor binding, and drug concentration at the effect site. This approach should provide evidence about whether dextromethorphan or dextrorphan, or both, are primarily responsible for the actions sought by abusers.

这个指导定量研究职业奖（K25）的长期目标是赞扬PI的职业准备，分析化学家，他需要成为一个成功的，独立的药物滥用研究人员的培训和研究经验。这将通过药物滥用药理学的培训和研究方案来实现，重点是药物动力学和行为药理学的先进领域。在本职业发展计划的最后阶段，这些不同的研究领域将被整合并用于采用药代动力学-药效学（PK-PD）建模进行研究。导师和共同导师都是药物滥用研究人员，在这些领域具有丰富的研究经验。该研究培训建议的目的是研究美沙芬作为滥用药物的药理学作用。右美沙芬是感冒和咳嗽药物的一种常见成分，是青年中越来越多地滥用的俱乐部药物（“robo”），经常伪装成更受欢迎的药物，如MDMA（“摇头丸”）或γ-羟基丁酸酯（“GHB”）。申请方将研究右啡烷（右美沙芬的主要活性代谢产物）作为负责右美沙芬苯环利定样作用的药物的作用。由于美沙芬在肝脏中广泛代谢为右啡烷，首过效应在其代谢中起重要作用。为了检验经口和静脉给予美沙芬将产生独特的行为-时间曲线的假设，将在大鼠中研究自发运动活动的剂量-反应和时间-过程研究。同时，将测定美沙芬和代谢产物的血清浓度-时间曲线。将使用响应-时间和浓度-时间曲线的PK-PD建模来确定体内药效学参数，例如内在疗效、估计的药物-受体结合和作用部位的药物浓度。这一方法应提供证据，说明是否美沙芬或右啡烷，或两者，主要负责的行动，寻求滥用者。