体外Caco-2细胞模型在药物吸收中的应用进展

目的:介绍Caco-2细胞模型的特征及其在药物吸收中的应用.方法:分析国内外近期相关文献,对Caco-2细胞模型在药物吸收动力学中的研究进行概述.结果:Caco-2细胞模型用于药物动力学研究,可预测药物在体内的吸收和代谢.结论:体外Caco-2细胞模型在药物吸收过程的研究中有重要意义.     

Caco-2细胞模型在药物研究中的应用

Caco2细胞模型广泛用于药物的吸收、代谢以及毒性研究,Caco2细胞模型作为药物吸收研究的一种快速筛选工具,在抗癌药物、无机药物、中药的研究方面得到了广泛的应用,成为药物研究的重要手段。     

Caco-2细胞模型在口服药物吸收研究中的应用

目的对Caco 2细胞模型在口服药物肠吸收研究中的应用作一综述。方法在引用了自1974~2004年的32篇文献的基础上,通过介绍并比较体外Caco 2模型和体内药物吸收转运的不同途径,讨论Caco 2单层细胞模型在预测不同类药物体内吸收中的作用。结果Caco 2细胞模型可以预测不同转运途径的药物体内吸收,尤其适用于被动转运药物,这一细胞模型在药物吸收机制、处方组成透膜性和黏膜毒性、药物吸收过程中的相互作用、药物的化学结构和体内转运关系、药物吸收限速因素、药物代谢稳定性及pH对药物吸收的影响等研究中均有较广泛的应用。结论Caco2细胞模型用于预测各种途径的药物吸收,在细胞水平上提供了大量与吸收相关的信息,是口服药物高通量筛选的良好工具。     

Caco-2细胞模型在药物研究中的应用

近年来,利用人结肠癌上皮细胞Caco-2（Human cocloncarcinoma cell lines）模型在药物研究方面取得了令人鼓舞的进展。由于药物透过Caco-2单细胞层的体外过程与药物口服后在肠中的吸收和代谢有良好的相关性,该模型已广泛用于药物在吸收、转运、代谢等方面的研究,现就Caco-2细胞模型在药物研究中的应用作一综述。     

Caco-2细胞系及其在药物吸收、代谢中的应用

由于小肠的生理结构适用于药物吸收 ,所以口服给药是最广泛、最方便的给药途径之一 ,因此研究药物在肠道的吸收与代谢就显得十分必要。目前用于药物吸收的实验方法主要有 :在体肠回流法 ,肠襻法 ,分离肠粘膜法、外翻囊法等 [1 ]。由于这些方法存在采用动脉组织及其它一些局限性 ,近年来人们尝试使用人肠细胞培养系统来研究药物在肠道的吸收和代谢 ,以快速筛选口服药物。Caco-2细胞模型被认为是目前最好的体外吸收模型 ,可用于快速评估新药的细胞渗透性、阐明药物转运的途径、评价提高膜通透性的方法、确定被动扩散的药物最合适的理化性质和…     

Caco-2细胞模型在药物动力学研究中的应用

药物动力学研究中 ,涵盖着吸收、分布、生物转化和排泄四个过程。口服给药是临床最常见的途径 ,药物发挥作用 ,关键在于吸收。吸收过程和排泄过程的研究对药物动力学而言至关重要。近年来 ,通过肠上皮细胞的培养来作为研究药物吸收、代谢机制的体外模型取得令人鼓舞的进展。最具有代表性的细胞是来自结肠癌细胞系的Caco 2细胞 (thehumancolonadenocarcinomacelllines的简称 )。研究发现了药物透过Caco 2单细胞层的体外过程与药物口服后在肠中的吸收和代谢有良好的相关性 ,使得Caco 2细胞成为研究药物吸收和代谢的最经典的体外细胞模型[1,2…     

Caco-2细胞模型在药物吸收研究中的应用

Caco-2细胞(thehumancoloncarcino-maline)模型是最近十几年来国外广泛采用的一种研究药物肠吸收的体外模型,它具有如下优点:与动物试验相比,培养细胞要比培养动物更省时更经济;可测定药物的细胞摄取及胯膜转运;Caco-2细胞内有药物代谢酶,可在有代谢状况下测定药物的胯膜转运;Caco-2细胞易于培养且生命力强;Caco-2细胞来源是人结肠癌细胞,同源性好;可用于区分肠腔内不同吸收途径的差别。1.Caco-2细胞模型建立Caco-2细胞适宜在37℃、含5%CO2的环境中培养,采用DMEM培养基,且在培养基中应含有10%胎牛血清、1%非必需氨基酸、1%谷氨酰胺和青…     

Caco-2细胞模型——药物吸收研究的有效“工具”

吸收过程是决定口服药物生物利用度的重要因素 ,然而很多药物的吸收机制还不明确。Caco 2细胞模型是目前最好的体外吸收模型 ,在药物的吸收过程及吸收机制的研究方面有广泛的应用 ,尤其在中药吸收研究方面 ,Caco 2细胞模型的应用成为目前的热点。另外 ,Caco 2细胞模型在药物代谢方面也有应用。因此 ,Caco 2细胞模型将成为药物吸收研究的重要手段 ,有助于加快新药筛选和开发的速度。     

Caco-2细胞在药物研究中的应用进展

目的Caco-2细胞模型特征及其在药物研究中的应用。方法概述了近年来Caco-2细胞模型在药物吸收机制、高通量筛选、药物相互作用、代谢及在药物剂型开发中应用情况。结果Caco-2细胞模型与整体吸收具有良好的相关性,可预测药物在体内的吸收、代谢规律。结论Caco-2细胞模型是药物体外研究的良好工具。     

Caco-2细胞模型在药物体外研究中的应用

Caco-2细胞模型是一种筛选药物离体口服特性的模型,已广泛用于评价药物在小肠的吸收特性和各种转运机制的研究.现综述Caco-2细胞单层模型的基本特点及其在药物的小肠吸收、代谢以及高通量筛选等方面的应用.     

Epithelial Toxicity of Alkylglycoside Surfactants

Alkylglycoside surfactants have been proposed as drug delivery excipients with the potential to enhance mucosal drug absorption of therapeutic macromolecules. Previous work reported their drug absorption‐promoting potential by demonstrating that several compounds within this class of surfactants improve mucosal absorption of peptides, proteins and other macromolecules. However, detailed investigation of their toxicity has not been conducted. Using Calu‐3 epithelial cell layers as a model of the airway mucosa, and liposomes as models of cell membranes, this work investigates the cytotoxicity of dodecylmaltoside, tridecylmaltoside and tetradecylmaltoside, as representative alkylglycosides. A combination of different toxicity assays and other tests indicating cell membrane disruption were used to assess cytotoxicity. The alkylglycosides tested induced a dramatic reduction in cell viability, cell membrane and liposome‐disruptive effects, as well as abrogation of transepithelial electrical resistance that did not recover completely. Importantly, these phenomena were noted at concentrations markedly lower than those typically used in the literature studies demonstrating the absorption‐enhancing properties of alkylglycosides. This work therefore demonstrates that alkylglycosides exhibit significant toxicity towards airway epithelial cells, most likely resulting from a membrane‐damaging effect, highlighting a need for further evaluation of their safety as absorption‐enhancing excipients.     

The use of human nasal in vitro cell systems during drug discovery and development.

The nasal route is widely used for the administration of drugs for both topical and systemic action. At an early stage in drug discovery and during the development process, it is essential to gain a thorough insight of the nasal absorption potential, metabolism and toxicity of the active compound and the components of the drug formulation. Human nasal epithelial cell cultures may provide a reliable screening tool for pharmaco-toxicological assessment of potential nasal drug formulations. The aim of this review is to give an overview of the information relevant for the development of a human nasal epithelial cell culture model useful during drug discovery and development. A primary goal in the development of in vitro cell culture systems is to maintain differentiated morphology and biochemical features, resembling the original tissue as closely as possible. The potential and limitations of the existing in vitro human nasal models are summarized. The following topics related to cell culture methodology are discussed: (i) primary cultures versus cell lines; (ii) cell-support substrate; (iii) medium and medium supplements; and (iv) the air-liquid interface model versus liquid-liquid. Several considerations with respect to the use of in vitro systems for pharmaceutical applications (transport, metabolism, assessment of ciliary toxicity) are also discussed.     

Development of an ADME and drug–drug interactions knowledge database for the acceleration of drug discovery and development

It is widely recognised that predicting or determining the absorption, distribution, metabolism and excretion (ADME) properties of a compound as early as possible in the drug discovery process helps to prevent costly late-stage failures. Although in recent years high-throughput in vitro absorption distribution metabolism excretion toxicity (ADMET) screens have been implemented, more efficient in silico filters are still highly needed to predict and model the most relevant metabolic and pharmacokinetic end points, and thereby accelerate drug discovery and development. The usefulness of the data generated and published for the chemist, biologist or project manager who ultimately wants to understand and optimise the ADME properties of lead compounds cannot be argued with. Collecting and comparing data is an overwhelming task for the time-pressed scientist. Aureus Pharma provides a uniquely specialised solution for knowledge generation in drug discovery. AurSCOPE^® ADME/DDI (drug–drug interaction) is a fully annotated, structured knowledge database containing all the pertinent biological and chemical information on the metabolic properties of drugs. This Aureus knowledge database has proven to be highly useful in designing predictive models and identifying potential drug–drug interactions.     

Building predictive ADMET models for early decisions in drug discovery

This review discusses the current challenges facing researchers developing computational models to predict absorption, distribution, metabolism, excretion and toxicity (ADMET) for early drug discovery. The strengths and weaknesses of different modeling approaches are reviewed and a survey of recent strategies to model several key ADMET parameters, including intestinal permeability, blood-brain barrier penetration, metabolism, bioavailability and drug toxicities, is presented.     

Mechanistic Approaches to Predicting Oral Drug Absorption

Modeling and simulation of oral drug absorption have been widely used in drug discovery, development, and regulation. Predictive absorption models are used to determine the rate and extent of oral drug absorption, facilitate lead drug candidate selection, establish formulation development strategy, and support the development of regulatory policies. This review highlights the development of recent drug absorption models including dispersion and compartmental models. The compartmental models include the compartmental absorption and transit model; Grass model; gastrointestinal transit absorption model; advanced compartmental absorption and transit model; and advanced dissolution, absorption, and metabolism model. Compared to the early absorption models, the above models developed or extended since the mid-1990s have demonstrated greatly improved predictive performance by accounting for multiple factors such as drug degradation, gastric emptying, intestinal transit, first-pass metabolism, and intestinal transport. For future model development, more heterogeneous features of the gastrointestinal tract (villous blood flow, metabolizing enzymes, and transporters), food effects, and drug–drug interactions should be fully characterized and taken into consideration. Moreover, predicting population inter- and intravariability in oral drug absorption can be useful and important for the evaluation of clinical safety and efficacy of drugs. Establishing databases and libraries that contain accurate pharmaceutical and pharmacokinetic information for commercialized and uncommercialized drugs may also be helpful for model development and validation.     

Human respiratory epithelial cell culture for drug delivery applications.

Recent developments in delivering drugs to the lung are driving the need for in vitro methods to evaluate the fate of inhaled medicines. Constraints on experimentation using animals have promoted the use of human respiratory epithelial cell cultures to model the absorption barrier of the lung; with two airway cell lines, 16HBE14o- and Calu-3, and primary cultured human alveolar type I-like cells (hAEpC) gaining prominence. These in vitro models develop permeability properties which are comparable to those reported for native lung epithelia. This is in contrast to the high permeability of the A549 human alveolar cell line, which is unsuitable for use in drug permeability experiments. Tabulation of apparent permeability coefficients (Papp) of compounds measured in 'absorptive' and 'secretory' directions reveals that fewer compounds (< 15) have been evaluated in 16HBE14o- cells and hAEpC compared to Calu-3 cells (> 50). Vectorial (asymmetric) transport of compounds is reported in the three cell types with P-glycoprotein, the most studied transport mechanism, being reported in all. Progress is being made towards in vitro-in vivo-correlation for pulmonary absorption and in the use of cultured respiratory cells to evaluate drug metabolism, toxicity and targeting strategies. In summary, methods for the culture of human respiratory epithelial cell layers have been established and data regarding their permeability characteristics and suitability to model the lung is becoming available. Discerning the circumstances under which the use of human respiratory cell models will be essential, or offers advantages over non-organ, non-species specific cell models, is the next challenge.     

Cell cultures as models for drug absorption across the intestinal mucosa.

This review deals with cell culture models for studies of drug absorption across the intestinal mucosa. The selection of appropriate cells and cell culture conditions is discussed, guidelines for the characterization of the cell models are presented, and the intestinal barriers to drug absorption are discussed and compared with those in the cell culture models. Finally, recent applications of the cell culture models in drug and peptide absorption and metabolism studies are reviewed.     

Precision-cut intestinal slices: alternative model for drug transport,metabolism, and toxicology research

Introduction: The absorption, distribution, metabolism, excretion and toxicity (ADME-tox) processes of drugs are of importance and require preclinical investigation intestine in addition to the liver. Various models have been developed for prediction of ADME-tox in the intestine. In this review, precision-cut intestinal slices (PCIS) are discussed and highlighted as model for ADME-tox studies.Areas covered: This review provides an overview of the applications and an update of the most recent research on PCIS as an ex vivo model to study the transport, metabolism and toxicology of drugs and other xenobiotics. The unique features of PCIS and the differences with other models as well as the translational aspects are also discussed.Expert opinion: PCIS are a simple, fast, and reliable ex vivo model for drug ADME-tox research. Therefore, PCIS are expected to become an indispensable link in the in vitro–ex vivo–in vivo extrapolation, and a bridge in translation of animal data to the human situation. In the future, this model may be helpful to study the effects of interorgan interactions, intestinal bacteria, excipients and drug formulations on the ADME-tox properties of drugs. The optimization of culture medium and the development of a (cryo)preservation technique require more research.