Tissue pharmacology imaging and modeling

项目3(组织建模项目)--项目摘要 一种成功的杀微生物剂产品具有影响预防药效学(PD)的药代动力学(PK)。 产品设计应该合理地处理候选成分、体积和药品包装 以产生目标PK/PD；但我们对这种关系的了解有限。此外，我们的方法用于 在动物和人类身上进行PK的实验评估是有限的：它们不能描述药物浓度 在药物起作用的靶室中的分布，并可能错过药物分配和 驱动药物转运的浓度梯度；它们无法测量关键分子，例如药物代谢物， 艾滋病毒，以及可能调节药物疗效的细胞内分子(例如，内源核苷酸)。因此，毒品 当代PK研究中的浓度虽然有用，但并不能充分地让我们了解产品PK和 可能不能准确地反映出真正的预防潜力。项目3将开发和应用新的方法- 实验和计算--为了理解和预测PK的这些关键的、迄今为止缺失的元素， 对于灌肠杀微生物剂产品，因为它正在由梦想计划设计和评估。我们的团队 在实验方法和计算模型方面具有协同专业知识，这是这里所需要的。 目标1和目标3发展了这种史无前例的、变革性的方法。AIM 1集成了详细的MALDI 大肠组织标本中药物、代谢物和其他关键分子的测定 应用共聚焦拉曼光谱的专用仪器--测定本地杀微生物剂 与光谱域光学相干层析成像相耦合的3D组织样品中的浓度 药物浓度对药物在其内迁移的粘膜组织结构的影响。Aim 3创造了一个新的 基于生物物理学和生理学的用于灌肠设计的详细PK的计算分区模型。它 预测这些隔室中与时间相关的3D药物浓度分布-用来描绘PK 比以前可能的分辨率更高。目标2和4，并将目标1和3的方法应用于人类 项目1和4中的研究以及项目2中的NHP研究，帮助解释PK和PD数据，并由此 了解、设计和选择最佳的杀微生物剂灌肠设计。

PROJECT 3 (TISSUE MODELING PROJECT) - PROJECT SUMMARY A successful microbicide product has pharmacokinetics (PK) that effect prophylactic pharmacodynamics (PD). Product design should manipulate candidate compositions, volumes, and drug packaging in a rational manner to yield target PK/PD; but we have limited understanding of this relationship. Further, our methods for experimentally evaluating PK in animals and humans are limited: they do not delineate drug concentration distributions throughout target compartments where the drugs act, and may miss drug partitioning and concentration gradients that drive drug transport; they fail to measure key molecules, e.g. drug metabolites, HIV, and intracellular molecules that might modulate drug efficacy (e.g. endogenous nucleotides). Thus, drug concentrations in contemporary PK studies, while useful, do not adequately inform us about product PK and may not accurately reflect true prophylactic potential. Project 3 will develop and apply new methodology - experimental and computational - to understand and predict these critical, heretofore missing elements of PK, for the enema microbicide product, as it is being designed and evaluated by the DREAM Program. Our team has synergistic expertise in both experimental methods and computational modeling of the kind needed here. Aims 1 and 3 develop this unprecedented, transformative methodology. Aim 1 integrates detailed MALDI measurements of drug, metabolite and other key molecules in colorectal tissue specimens with those by a specialized instrument that applies confocal Raman spectroscopy - to measure local microbicide drug concentrations in tissue specimens in 3D - coupled to spectral domain optical coherence tomography - to link drug concentration to structures of the mucosal tissue within which drug is migrating. Aim 3 creates a new biophysics and physiology based computational compartmental model of detailed PK for enema designs. It predicts the 3D, time-dependent drug concentration distributions in these compartments - delineating PK with greater resolution than previously possible. Aims 2 and 4 and apply the methods of Aims 1 and 3 to the human studies in Project 1 and 4 and NHP studies in Project 2, helping interpret PK and PD data, and thence understand, design and choose the best microbicide enema designs.