Precision-cut tissue slices (PCTS) are viable ex vivo explants of tissue with a reproducible, well defined thickness. They represent a mini-model of the organ under study and contain all cells of the tissue in their natural environment, leaving intercellular and cell-matrix interactions intact, and are therefore highly appropriate for studying multicellular processes. PCTS are mainly used to study the metabolism and toxicity of xenobiotics, but they are suitable for many other purposes. Here we describe the protocols to prepare and incubate rat and human liver and intestinal slices. Slices are prepared from fresh liver by making a cylindrical core using a drill with a hollow bit, from which slices are cut with a specially designed tissue slicer. Intestinal tissue is embedded in cylinders of agarose before slicing. Slices remain viable for 24 h (intestine) and up to 96 h (liver) when incubated in 6- or 12-well plates under 95% O(2)/5% CO(2) atmosphere.

Preparation and incubation of precision-cut liver and intestinal slices for application in drug metabolism and toxicity studies

Precision-cut liver slices: characteristics and use for in vitro pharmaco-toxicology.

This is the 54th report of a series of workshops organised by the European Centre for the Validation of Alternative Methods (ECVAM). The main objective of ECVAM, as defined in 1993 by its Scientific Advisory Committee, is to promote the scientific and regulatory acceptance of alternative methods which are of importance to the biosciences, and which reduce, refine or replace the use of laboratory animals. One of the first priorities set by ECVAM was the implementation of procedures that would enable it to become well informed about the state-of-the-art of non-animal test development and validation, and of opportunities for the possible incorporation of alternative methods into regulatory procedures. It was decided that this would be best achieved through a programme of ECVAM workshops, each addressing a specific topic, and at which selected groups of independent international experts would review the current status of various types of in vitro tests and their potential uses, and make recommendations about the best ways forward. A workshop on Metabolism: a bottleneck in in vitro toxicological test development, was held at ECVAM on 26–29 January 2004, with participants Metabolism: A Bottleneck in In Vitro Toxicological Test Development

Metabolism: a bottleneck in in vitro toxicological test development. The report and recommendations of ECVAM workshop 54.

The application of in vitro model systems to evaluate the toxicity of xenobiotics has significantly enhanced our understanding of drug- and chemical-induced target toxicity. From a scientific perspective, there are several reasons for the popularity of in vitro model systems. From the public perspective, in vitro model systems enjoy increasing popularity because their application may allow a reduction in the number of live animals employed in toxicity testing. In this review, we present an overview of the use of in vitro model systems to investigate target organ toxicity of drugs and chemicals, and provide selective examples of these model systems to better understand cutaneous and ocular toxicity and the role of drug metabolism in the hepatotoxicity of selected agents. We conclude by examining the value and use of in vitro model systems in industrial development of new pharmaceutical agents.

Predictive value of in vitro model systems in toxicology

Precision-cut tissue slices have been applied by many researchers because they represent an organ mini-model that closely resembles the organ from which it is prepared, with all cell types present in their original tissue-matrix configuration. Preparation and incubation methods of precision-cut tissue slices from various tissues are discussed and recommendations are given for optimal handling and culturing to retain optimal viability and functional integrity. The potential of precision-cut tissue slices from several organs to predict metabolite profiles and metabolic clearance of novel drugs, the involvement of transporters and the induction and inhibition of drug metabolism is discussed. To allow regular use of tissue slices in drug discovery and development, improvement of cryopreservation methods for precision-cut tissue slices is of great importance. It is concluded that the use of tissue slices in the pharmaceutical industry and in academic research can contribute significantly to obtain relevant information about metabolism and drug-drug interactions in various organs and pharmacokinetics of novel chemical entities in man, and thereby to the development of safe drugs.

Precision-cut tissue slices as a tool to predict metabolism of novel drugs

/nterdisciplinary Research Centre for Cell Modulation Studies, Faculty of Science and Health, University of East London, Romford Road, London E15 4LZ, UK; Sandoz Phanna Ltd, 4002 Basel, Switzerland; .sDepartment of Pharmacology, College of Medicine, University of Arizona, Tucson, AZ 85724, USA; /nstitut fiir Pharmakokinetik, Schering Aktiengesellschaft, 13342 Berlin, Germany; Department of Pharmacology and Toxicology, SLU Biomedical Centre, 751 23 Uppsala, Sweden; Der,artment of Pharmacy, University of Manchester, Oxford Road, Manchester M13 9PL, UK; Solvay Duphar, C.J. van Houlenlaan 36, 1380 DA Weesp, The Netherlands; BIBRA International, Woodmansterne Road, Carshalton, Surrey SM5 4DS, UK; Crop Protection Animal Metabolism and Residue Chemistry, BASF Aktiengesellschaft, 67114 Limburgerhof, Germany; Medical Countermeasures Section, Defence Research Establishment Suffield, Medicine Hat, Alberta TlA BK6, Canada; 13Department of Surgery, University of Edinburgh Medical School, Teviot Place, Edinburgh EHB 9AG, UK

The use of tissue slices for pharmacotoxicology studies : The report and recommendations of ecvam workshop 20

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The use of tissue slices for pharmacotoxicology studies : The report and recommendations of ecvam workshop 20