PHARMACOKINETIC/PHARMACODYNAMICS OF CNS THERAPY

对于拟议的工作，我们的意图是推导出药理 I/II期临床选定抗癌药物的信息 对中枢神经系统恶性肿瘤治疗的评价。即将推出的药物 研究和每项研究的范围将由计划确定 导演(迈克尔·普拉多斯医学博士)。这将是 药理学核心设施中的参与者与其他参与者进行互动 这个项目的调查人员。这样的互动将帮助我们建立联系 我们的药代动力学研究结果与生物效应和 中枢神经系统层面的作用机制。为了一个完整的药理学 研究，这项工作将包括两个阶段：(A)发展或 为测量实施适当的分析方法 可能的组织和生物体液。具体地说，高效液相或气相色谱 将建立化合物(如 如紫杉醇和替莫唑胺)正在研究中。开发适当的 方法学可能需要测定物理化学性质 如溶解度、药物与血浆蛋白结合和稳定性 不同温度下不同基质中的药物。这一阶段 在进入下一阶段之前，必须成功完成。(B) 该制剂的药代动力学/药效学表征 正在进行的临床评估将包括：最大血浆或脑脊液 血药浓度；血浆、脑脊液或尿清除量；表观体积 稳态分布；血浆(CSF)时间曲线下面积； 组织或脑脊液分布；调和平均血浆/脑脊液半衰期和 尿液排泄量百分比。将尝试将这些数据关联起来 药代动力学参数与观察到的生物效应，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，发展用于测量的分析方法 新陈代谢的发生，分析方法的发展 将继续进行代谢物的测量，以便平行 这些化合物的药代动力学/药效学测定可以是 与母体化合物一起进行。有限药代动力学 研究可能旨在回答某些特定的问题，即 与正在调查的药物的性质有关。对这方面的研究 类型可能涉及：(A)评价口服药物的生物利用度研究 行政管理。黄曲霉代谢物(S)的结构解析 毒品。这项工作可能包括有限的合成或大规模SPECT工作，以 建立未知药物的鉴别(C)血浆和血浆的研究 非人灵长类动物脑脊液药代动力学研究。

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.