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Predicting Intracellular Drug Concentrations In The Presence Of Transporters

预测存在转运蛋白的细胞内药物浓度

基本信息

批准号：
10734908
负责人：
Kenneth Ray Korzekwa
金额：
$ 35.22万
依托单位：
TEMPLE UNIV OF THE COMMONWEALTH
依托单位国家：
美国
项目类别：
财政年份：
2013
资助国家：
美国
起止时间：
2013-01-15 至 2027-07-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10734908
关键词：
Acids Active Biological Transport Adipocytes Artificial Membranes Automobile Driving Binding Blood flow Cell Membrane Permeability Cells Charge Convection Data Data Set Differential Equation Diffusion Discontinuous Capillary Dose Drug Kinetics Drug toxicity Endothelium Environment Enzymes Equation Erythrocytes Excipients Exhibits Funding Glycocalyx Goals Head Hepatocyte House mice Human Image In Vitro Intestines Kinetics Knock-out Literature Liver Measures Membrane Metabolism Methods Microdialysis Microfluidics Microsomes Modeling Mus Oral Organ Particle Size Perfusion Permeability Pharmaceutical Preparations Pinocytosis Plasma Polysorbate 80 Process Rattus Reaction Research Rodent Special Population Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization Techniques Testing Time Tissues Tube Work absorption aqueous base cost effective drug clearance drug development drug disposition drug distribution drug efficacy drug metabolism experimental study extracellular feeding improved in vivo mathematical methods mathematical model medication safety novel pharmacokinetic model physiologically based pharmacokinetics polar environment predictive modeling predictive tools uptake

项目摘要

Project Summary 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 2018-2022, we have made significant progress in developing models to predict drug volume of distribution, and models to predict drug absorption. We have used the basic principles underlying permeability and partitioning to build a new framework for PBPK models (termed PermQ). This framework now allows us to incorporate permeability-limited distribution, partitioning, organ blood flow, and active transport into PBPK models with explicit membrane kinetics. We have started to build upon our current work to develop novel frameworks to predict drug clearance, a new focus of this renewal. These new modeling paradigms, together with our time- and distance- dependent continuous absorption models, will provide markedly better predictions of intracellular concentrations in the presence of drug metabolizing enzymes and transporters, and will address an unmet critical need for cost effective drug development by providing novel predictive tools for drug pharmacokinetics in humans. Three specific aims are proposed. 1) New in vitro and mathematical methods will characterize the time-course of cellular permeability and partitioning, to inform mechanisms underlying drug distribution, absorption, and intracellular concentrations that drive drug clearance. Experiments in artificial membrane environments at various pH values will define the pH partitioning – membrane permeability relationship. In vitro microdialysis and transwell techniques will capture the time-course of drug partitioning into cells including MDCK, Caco-2, adipocytes, and hepatocytes. Partitioning into erythrocyte glycocalyx will be measured. Resulting data will be used as inputs to develop mathematical models to predict drug permeability across single vs. multiple membranes across a cell, and drug partitioning into membranes. 2) Excipient effects on oral absorption will be predicted in humans and rodents. Effect of excipient dose-dependent (Polysorbate 80 and PEG400) inhibition of intestinal drug metabolizing enzymes and transporters (DMETs) will be evaluated with a refined rat intestinal model. A continuous intestinal mouse absorption model will be developed and refined. The human and rat intestinal models will be interfaced with species-specific PermQ models. 3) New in vitro and mathematical methods will improve predictions of drug clearance. Rat data will be collected with microfluidics in hepatocytes and in vivo, with regional drug quantification with MALDI imaging. Three standard liver models – well-stirred (WSM), parallel-tube (PTM), and dispersion (DM) – will be evaluated within human and rat PermQ. Enzyme zonation within the liver sinusoid will be modeled with both literature (discretized) and new partial differential equation (continuous) methods.

项目摘要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2018-2022年的筹资期间，我们在以下方面取得了重大进展开发预测药物分布体积的模型，以及预测药物吸收的模型。我们已经使用了建立新的PBPK模型框架的渗透性和分割的基本原理 (称为PermQ)。这个框架现在允许我们将渗透率受限的分布、分区、器官血流和主动转运到具有显式膜动力学的PBPK模型。我们已经开始在我们目前工作的基础上，开发新的框架来预测药物清除率，这是这方面的新重点更新。这些新的建模范例，以及我们依赖于时间和距离的连续吸收模型，将提供明显更好的预测细胞内浓度的存在药物代谢酶和转运体，并将解决对具有成本效益的药物的未得到满足的迫切需求通过为药物在人类体内的药代动力学提供新的预测工具来开发。提出了三个具体目标。1)新的体外和数学方法将表征时间过程细胞渗透性和分配，以告知潜在的药物分布，吸收和机制推动药物清除的细胞内浓度。在人工膜环境中的实验不同的pH值将决定pH分配-膜透过率的关系。体外微透析 Transwell技术将捕捉药物分配到细胞中的时间过程，包括MDCK，Caco-2，脂肪细胞和肝细胞。将测量到红细胞糖萼的分配率。生成的数据将是用作输入以开发数学模型，以预测药物在单药和多药之间的渗透性穿过细胞的膜，以及药物分割成膜。2)赋形剂对口服吸收的影响在人类和啮齿动物身上预测到的。赋形剂(聚山梨酯80和聚乙二醇400)的剂量依赖性抑制作用肠道药物代谢酶和转运体(DMET)的含量将通过精制的大鼠肠道进行评估模特。将建立和完善小鼠连续肠道吸收模型。人和老鼠肠道模型将与特定物种的PermQ模型对接。3)新的体外和数学这些方法将提高对药物清除的预测。大鼠的数据将通过肝细胞中的微流体收集在体内，用MALDI成像进行局部药物定量。三种标准肝脏模型-搅拌充分 (WSM)、平行管(PTM)和分散度(DM)-将在人和大鼠PermQ中进行评估。酶将使用文献(离散化)和新的偏导数来模拟肝窦内的带状结构方程(连续)方法。

项目成果

期刊论文数量（6）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Compartmental models for apical efflux by P-glycoprotein--part 1: evaluation of model complexity.

p-糖蛋白的顶端外排的隔室模型 - 部分：模型复杂性的评估。

DOI：
10.1007/s11095-013-1164-7
发表时间：
2014-02
期刊：
PHARMACEUTICAL RESEARCH
影响因子：
3.7
作者：
Nagar, Swati;Tucker, Jalia;Weiskircher, Erica A.;Bhoopathy, Siddhartha;Hidalgo, Ismael J.;Korzekwa, Ken
通讯作者：
Korzekwa, Ken

ITC recommendations for transporter kinetic parameter estimation and translational modeling of transport-mediated PK and DDIs in humans.