Simulated Human Pharmacokinetics in Rat: Methylphenidate

描述（由申请人提供）：目前大多数证据支持使用哌甲酯等兴奋剂作为注意缺陷多动障碍的最有效治疗方法。不幸的是，兴奋剂的治疗作用的准确评估，以及替代治疗策略的发展，受到限制的神经元机制，暴露于这些药物的临床相关剂量的影响的理解。在评估动物模型的相关性以研究这些药物的作用时，一个主要问题是很难将人类和实验动物的药物暴露条件等同起来。治疗条件对药物的神经生物学反应的深刻影响已被广泛记录，因此药物使用的动物模型的转化效用关键取决于暴露曲线模拟人类条件的程度。为了提高动物模型的潜在转化价值，我们正在开发一种静脉给药方法，该方法能够在大鼠中近似人血浆药物浓度的时间曲线。本提案的重点是完善该方法，以模拟与注意缺陷多动障碍药物治疗相关的口服哌甲酯后血浆浓度的时间曲线。暴露特征将包括：血浆哌甲酯逐渐增加，以接近口服给药相关的药物升高;与治疗有效性相关的全天恒定或升高的血浆水平;以及血浆药物逐渐下降，对应于约3小时的人血浆半衰期。然后，我们将应用这种方法在大鼠多学科研究中使用体内微透析和5选择系列反应时间任务来测试的假设，即一天内耐受性的疗效，似乎发生时，保持恒定的血浆水平的哌甲酯将反映在减少额皮质细胞外去甲肾上腺素的反应和相应的减少注意力的表现。这些研究的结果将有重要的意义，了解哌甲酯发挥其治疗作用的机制，并将提供一个基础和背景，为后续的研究，针对该药物发挥其治疗作用的机制。

DESCRIPTION (provided by applicant): Most current evidence supports the use of stimulants such as methylphenidate as the most effective treatment for Attention Deficit Hyperactivity Disorder. Unfortunately, an accurate appraisal of the therapeutic actions of stimulants, as well as the development of alternative treatment strategies, are hampered by limited understanding of the neuronal mechanisms that are affected by exposure to clinically relevant doses of these drugs. One major problem in assessing the relevancy of animal models to study the effects of these drugs is the difficulty in equating drug exposure conditions in humans and experimental animals. The profound effect of treatment conditions on the neurobiological responses to drugs has been extensively documented, and thus the translational utility of an animal model of drug usage critically depends on the degree to which the exposure profile simulates the human conditions. To enhance the potential translational value of animal models, we are developing an intravenous drug delivery methodology which enables an approximation in rats of the temporal profile of human plasma drug concentrations. The focus of the present proposal is to refine this methodology to simulate the temporal profile of plasma methylphenidate concentrations following oral administration that has been associated with the pharmacotherapy of Attention Deficit Hyperactivity Disorder. The exposure profile will include: a gradual increase in plasma methylphenidate to approximate the rise in drug associated with oral administration; day-long, constant or ascending plasma levels that have been associated with therapeutic efficacy; and the gradual decline in plasma drug corresponding to the human plasma half-life of about three hours. We will then apply this approach in rats in multidisciplinary studies using in vivo microdialysis and the 5-choice serial reaction time task to test the hypothesis that within-day-tolerance in efficacy that appears to occur when constant plasma levels of methylphenidate are maintained will be reflected in a decrease in the frontal cortex extracellular norepinephrine response and a corresponding decrease in attentional performance. The results of these studies will have important implications for understanding the mechanisms by which methylphenidate exerts its therapeutic effects and will provide a foundation and context for subsequent studies directed at the mechanisms by which this drug exerts its therapeutic effects.