PHARMACOKINETIC/PHARMACODYNAMICS OF CNS THERAPY

对于拟议的工作，我们的目的是获得药理学 I/II期临床试验中选定抗癌药物的信息 评价CNS恶性肿瘤的治疗。 这些药物 研究和每项研究的范围将由该计划确定 主任（Michael Prados，医学博士）。 这将是我们的主要目标之一， 药理学核心设施的参与者与其他参与者互动 这个项目的调查员。 这样的互动将帮助我们 我们的药代动力学发现， 在CNS水平的作用机制。 对于完整的药理学 研究，工作将包括两个阶段：（a）开发或 采用适当的分析方法进行测量 可能的组织和生物液体。 具体而言，HPLC或GC 将建立用于定量化合物的方法（例如 如紫杉醇和替莫唑胺）。 发展适当的 方法学可能需要测定物理化学性质 例如溶解度、药物与血浆蛋白结合和稳定性 在不同温度下的不同基质中的药物。 这个阶段 在进入下一阶段之前，必须成功完成。 （B） 药物的药代动力学/药效学表征 接受临床评价的将包括：最大血浆或CSF 浓度;血浆、CSF或尿液清除率;表观体积 稳态分布;血浆（CSF）时间曲线下面积; 组织或CSF分布;调和平均血浆/CSF半衰期和 尿排泄百分比。 将尝试将这些关联起来 药代动力学参数与观察到的生物学效应，如 毒性和/或反应数据。 一般来说，这些研究将局限于 与母体药物的关系 然而，在大量新陈代谢的情况下， 发生，发展分析方法的测量， 代谢发生，分析方法的发展， 将进行代谢物的测量， 这些化合物的药代动力学/药效学测定可 与母体化合物一起沿着进行。 有限药代动力学 研究可以针对回答某些特定的问题， 与被研究药物的性质有关。 对此的研究 类型可能包括：（a）生物利用度研究，以评估口服药物 局 药物代谢产物的结构解析 药 这项工作可能包括有限的合成或质量Spect工作， 确定未知药物的鉴别（c）血浆研究， 非人灵长类动物的CSF药代动力学。

For the proposed work, it is our intent to derive pharmacological information on selected anticancer agents in phase I/II clinical evaluation for the treatment of CNS malignancies. The drugs to be studied and the extent of each study will be determined by the Program Director (Michael Prados, M.D.). It will be one of the prime goals for participants in the pharmacology core facility to interact with the other investigators on this project. Such interactions will help us to relate our pharmacokinetic findings to the biological effects and to the mechanisms of action at the CNS level. For a complete pharmacological study, the work will consist of two phase: (a) Development or implementation of a suitable analytical methodology for the measurement of likely tissue and biological fluids. Specifically, HPLC or GC methodologies will be established for quantitation of the compound (such as taxol & temozolomide) being studied. Development of appropriate methodologies may require determination of physicochemical properties such as solubilities, binding of drug to plasma proteins and stability of the drugs in various matrixes at various temperatures. This phase must be successfully completed before entering into the next phase. (b) Characterization of the pharmacokinetics/pharmacodynamics of the agent undergoing clinical evaluation will include: maximum plasma or CSF concentration; plasma, CSF or urinary clearance; apparent volume of distribution at steady state; area under the plasma (CSF) time curve; tissue or CSF distribution; harmonic mean plasma/CSF half-lives and percent urinary excretion. Attempts will be made to correlate these pharmacokinetic parameters with the observed biological effects such as toxicity and/or response data. Generally these studies will be confined to the parent drug. However, in instances where extensive metabolism occurs, the development of analytical methodology for measurement of the metabolism occurs, the development of analytical methodology for measurement of the metabolites will be pursued so that parallel pharmacokinetic/pharmacodynamic determinations of these compounds can be conducted along with the parent compound. Limited pharmacokinetic studies may be directed at answering certain specific questions that relate to the properties of the drug being investigated. Studies of this type could involve: (a) bioavailability study to evaluate a drug for oral administration. Elucidation of the structure of metabolite(s) of the drug. This effort may include limited synthetic or Mass Spect work to establish the identify of the unknown drug (c) study of the plasma and CSF pharmacokinetics in nonhuman primates.