MODELS OF HEPATOBILIARY XENOBIOTIC DISPOSITION IN AGING

数学模型，与生物实验紧密结合，可以 发展为（1）描述生物医学研究中的复杂动态过程， (2)检验假设，（3）提高预测能力，（4）外推 实验观察到未经测试的条件，（5）尽量减少使用 实验动物以有效的方式。 建议的目标 研究的目的是建立能够预测变化的数学模型， 在老化过程中异生物质的肝胆处置。 肝脏 在解毒（或激活）和消除 毒品和环境毒素 肝胆外源性物质的变化 在发育和老化过程中的处置已经记录了许多 基质和物种，并且是评估 新化学实体的治疗和/或毒性潜力。 先前 调查的范围往往很窄， 动物（主要是哺乳动物）实验。 这些研究提供了 对年龄依赖性变化的机制有价值的见解， 药物和毒素的肝脏处置，但已证明只有一个 有限的能力来推断这一机制的信息，以其他 物种或化合物。 如本提案所述， 方程将被写入模型的离散过程， 肝胆异生物质处置（肝摄取、肝储存和 结合、生物转化、肝脏排出、胆汁排泄和 肝肠再循环）。 这些公式将基于 生化（代谢、运输）和生理（器官体积、血液 流量）参数。 在模型中纳入生理参数 将有助于描述衰老过程中的性格变化，并将 有助于将模型外推到其他哺乳动物物种。 此外，通过提供一组定义明确的参数（例如，率 生物转化，胆汁排泄），必须确定任何给定的 该模型的应用将有助于设计高效的 实验，以阐明肝胆处置的未测试 化合物. 肝胆外源性处置（包括肠肝 回收）太复杂，无法用数学方法全面模拟。 模型，或仅通过体外技术进行评价，而无需借助 哺乳动物系统 Fischer-344大鼠（选定年龄）将作为 建立数学模型的基础。 两个原型 底物，丙戊酸和吗啡，代表两种不同的类别 将用于模型开发。 一 多实验方法，采用各种体外（细胞和 亚细胞）和原位技术，将用于检查每个 参与肝胆异生物质处置的过程， 数学模型的参数估计。 模型试验和 在适当的哺乳动物系统中进行验证是 发展与人类有关的生物系统的数学模型 生理学和/或疾病。 模型正确预测的能力 将在有限体内测试每种基质的分布 实验 两种原型的文献中可用的数据将 用于评估模型外推到其他物种的能力。 总之，本项目开发的数学模型将最大限度地提高 使用从体外系统收集的数据（例如，人肝细胞）。 更重要的是，这些模型将提供一种方法， 关于离散过程中年龄依赖性改变的机械知识 将肝胆处置控制为肝的合理外推 不同发育阶段和物种间的异生物质处置（包括 人类），并将减少所需的脊椎动物的数量， 利用其他底物和/或动物物种的未来研究。

Mathematical models, closely coupled to biologic experimentation, can be developed to (1) describe complex dynamic processes in biomedical research, (2) test hypotheses, (3) improve predictive abilities, (4) extrapolate experimental observations to untested conditions, and (5) minimize the use of experimental animals in an effective manner. The goal of the proposed research is to construct mathematical models capable of predicting changes in the hepatobiliary disposition of xenobiotics during aging. The liver plays a key role in the detoxification (or activation) and elimination of drugs and environmental toxins. Alterations in hepatobiliary xenobiotic disposition during development and aging have been documented for many substrates and species, and are an important consideration in assessing the therapeutic and/or toxic potential of new chemical entities. Previous investigations have tended to be narrow in scope and to rely on intensive animal (primarily mammalian) experimentation. Such studies have provided valuable insights into the mechanism underlying age-dependent changes in hepatic disposition of drugs and toxins, but have demonstrated only a limited ability to extrapolate this mechanistic information to other species or compounds. As described in this proposal, differential equations will be written to model the discrete processes governing hepatobiliary xenobiotic disposition (hepatic uptake, hepatic storage and binding, biotransformation, hepatic egress, biliary excretion and enterohepatic recirculation). These equations will be based upon both biochemical (metabolism, transport) and physiologic (organ volume, blood flow) parameters. Incorporation of physiologic parameters in the model will assist in describing dispositional changes during aging, and will facilitate extrapolation of the model to other mammalian species. Moreover, by providing a well-defined set of parameters (e.g., rate of biotransformation, biliary excretion) that must be determined for any given substrate, application of this model will assist in the design of efficient experiments to elucidate the hepatobiliary disposition of untested compounds. Hepatobiliary xenobiotic disposition (including enterohepatic recycling) is too complex to be simulated comprehensively by mathematical models, or evaluated solely by in vitro techniques, without the aid of mammalian systems. The Fischer-344 rat (at selected ages) will serve as the basis for development of the mathematical model. Two prototype substrates, valproic acid and morphine, representing two distinct classes of chemical compounds, will be used in model development. A multiexperimental approach, employing various in vitro (cellular and subcellular) and in situ techniques, will be utilized to examine each process involved in hepatobiliary xenobiotic disposition and to obtain parameter estimates for the mathematical model. Model testing and validation in an appropriate mammalian system is an essential part of developing mathematical models of biologic systems that pertain to human physiology and/or disease. The ability of the model to predict correctly the disposition of each substrate will be tested in limited in vivo experiments. Data available in the literature for both prototypes will be used to assess the capability of the model to extrapolate to other species. In summary, the mathematical models developed in this project will maximize the use of data collected from in vitro systems (e.g., human hepatocytes). More importantly, these models will provide a method to translate mechanistic knowledge about age-dependent alterations in discrete processes governing hepatobiliary disposition into rational extrapolations of hepatic xenobiotic disposition across developmental stages and species (including human), and will reduce the number of vertebrate animals required for future investigations utilizing other substrates and/or animal species.