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兴奋剂，如哌甲酯，作为治疗注意缺陷多动障碍最有效的方法。不幸的是，对兴奋剂治疗作用的准确评估以及替代治疗策略的发展，由于对暴露于临床相关剂量的这些药物所影响的神经元机制的了解有限而受到阻碍。在评估动物模型与研究这些药物影响的相关性时，一个主要问题是难以将人类和实验动物的药物暴露条件等同起来。治疗条件对药物神经生物学反应的深远影响已被广泛记录，因此药物使用动物模型的转化效用严重依赖于暴露概况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，该方法可以在大鼠中近似人类血浆药物浓度的时间分布。本研究的重点是改进这一方法，模拟口服哌甲酯后血浆浓度的时间分布，这与注意缺陷多动障碍的药物治疗有关。暴露情况将包括：血浆哌甲酯剂量逐渐增加，与口服给药时药物剂量的增加接近；与治疗效果相关的全天、恒定或升高的血浆水平；并在血浆中逐渐下降，对应人血浆半衰期约为3小时。然后，我们将这种方法应用于大鼠的多学科研究中，使用体内微透析和5选择连续反应时间任务来测试假设，即当维持恒定的血浆哌甲酯水平时，可能出现的日间疗效耐受性将反映在额叶皮层细胞外去甲肾上腺素反应的减少和注意力表现的相应下降上。这些研究结果将对理解哌甲酯发挥其治疗作用的机制具有重要意义，并将为后续针对该药物发挥其治疗作用的机制的研究提供基础和背景。

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.