Predicting intracellular drug concentrations in the presence of transporters

拟议研究的首要目标是预测细胞内和细胞外的浓度- 使用包括膜分割、膜通透性、器官血流量、 主动运输和新陈代谢。在2013-2016年的筹资期间，我们在以下方面取得了重大进展 将显式膜间隔纳入预测模型，我们已经深入评估了 不同膜几何形状及相关因素对细胞内浓度预测的影响。我们是 现在使用渗透性和划分的基本原理来构建PBPK的新框架 模特们。这将使我们能够将渗透性有限的分布、分区、器官血流和 主动转运到具有显式膜动力学的PBPK模型(MePBPK)。这一新的模式将 提供明显更好的细胞内浓度预测，并将解决尚未满足的关键需求 通过为人类体内的药物处置提供新的预测工具，进行具有成本效益的药物开发。 提出了三个具体目标。1)新的生物物理方法将被用来研究细胞动力学 药物渗透性和分配性。具体来说，将使用新的细胞显微镜技术来评估 细胞分布的时间进程和在单层中进行细胞渗透性研究，以及一系列 将评估在当前资助期内开发的显式膜模型的能力 量化观察到的膜、细胞器和细胞分布动力学。2)开发新的框架 包含膜分区的PBPK和混合室-PBPK模型，渗透率受限 弥散和器官血流量(MePBPK)。组件包括用于混合和混合的器官特定模型 完整的PBPK方法，以及使用我们公布的对流-扩散-反应方法的吸收模型。 这些模型将在AIM 3中使用，以结合主动摄取/外排运输和代谢来预测 胞内和胞外浓度-时间分布。3)来自大鼠和人类的活体实验数据将 用于扩展和验证模型以预测细胞内和细胞外药物浓度的时间进程。 我们将重点模拟药物在肝脏中的处置和药物在肝脏中的吸收。 胃肠道中存在转运体和药物代谢酶。

The overarching goal of the proposed research is to predict the intracellular and extracellular concentration- time profiles using models that include membrane partitioning, membrane permeability, organ blood flow, active transport, and metabolism. In the funding period from 2013-2016, we have made significant progress in incorporating explicit membrane compartments into predictive models, and we have evaluated in depth the impact of various membrane geometries and related factors on intracellular concentration prediction. We are now using the basic principles underlying permeability and partitioning to build a new framework for PBPK models. This will allow us to incorporate permeability-limited distribution, partitioning, organ blood flow, and active transport into PBPK models with explicit membrane kinetics (memPBPK). This new paradigm will provide markedly better predictions of intracellular concentrations, and will address an unmet critical need for cost effective drug development by providing novel predictive tools for drug disposition in humans. Three specific aims are proposed. 1) Novel biophysical methods will be used to study the cellular kinetics of drug permeability and partitioning. Specifically, novel cell microscopy techniques will be used to evaluate the time-course of cellular distribution and conduct cellular permeability studies in monolayers, and a range of explicit membrane models developed during the current funding period will be evaluated for their ability to quantify the observed membrane, organelle, and cellular distribution kinetics. 2) Develop a new framework for PBPK and hybrid compartmental-PBPK models that incorporate membrane partitioning, permeability-limited diffusion, and organ blood flow (memPBPK). Components include organ-specific models for use in hybrid and full PBPK approaches, and models for absorption using our published convection-diffusion-reaction approach. These models will be used in Aim 3 to incorporate active uptake/efflux transport and metabolism to predict intra- and extracellular concentration-time profiles. 3) In vivo experimental data from rats and humans will be used to expand and validate models to predict the time course of intra- and extracellular drug concentrations. We will focus on modeling the disposition of drugs in the liver and the absorption of drugs from the gastrointestinal tract in the presence of transporters and drug metabolizing enzymes.