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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浓度- 使用包括膜分配，膜渗透性，器官血流，主动运输和新陈代谢。在2018-2022年的资助期内，我们在以下方面取得了重大进展：开发预测药物分布容积的模型和预测药物吸收的模型。我们已经使用渗透性和分配的基本原则，以建立PBPK模型的新框架（称为PermQ）。这个框架现在允许我们将渗透率限制的分布，分区，器官血流量和主动转运到具有明确膜动力学的PBPK模型中。我们已经开始建立在我们目前的工作，开发新的框架来预测药物清除，这是一个新的焦点，退款这些新的建模范例，连同我们的时间和距离相关的连续吸收模型，将提供明显更好的预测细胞内浓度的存在下，药物代谢酶和转运蛋白，并将解决未满足的关键需求，成本效益的药物通过为人类药物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进程细胞渗透性和分配，以告知药物分布，吸收和代谢的潜在机制。驱动药物清除的细胞内浓度。人工膜环境中的实验. 不同的pH值将限定pH分配-膜渗透性关系。体外微透析 transwell技术将捕获药物分配到包括MDCK，Caco-2，脂肪细胞和肝细胞。将测量红细胞糖萼的分配。产生的数据将是用作开发数学模型的输入，以预测单次与多次给药的药物渗透性细胞膜，药物分配到细胞膜。2)辅料对口服吸收的影响将是在人类和啮齿动物中预测。辅料剂量依赖性（聚山梨酯80和PEG 400）抑制作用肠道药物代谢酶和转运蛋白（DMET）将用精制的大鼠肠道模型将开发和完善小鼠肠道连续吸收模型。人和大鼠肠道模型将与物种特异性PermQ模型连接。3)新的体外和数学方法将改善药物清除的预测。将在肝细胞中使用微流体收集大鼠数据在体内，用MALDI成像进行局部药物定量。三个标准肝脏模型-充分搅拌 (WSM)平行管（PTM）和分散（DM）-将在人和大鼠PermQ中进行评价。酶肝窦状隙内的分区将使用文献（离散化）和新的偏微分进行建模方程（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.