The Use of Long-term Hepatocyte Cultures for Detecting Induction of Drug Metabolising Enzymes: The Current Status ECVAM Hepatocytes and Metabolically Competent Systems Task Force Report 1 Sandra Coecke, 1 Vera Rogiers, 2 Martin Bayliss, 3 José Castell, 4 Johannes Doehmer, 5 Gérard Fabre, 6 Jeffrey Fry, 7 Armin Kern 8 and Carl Westmoreland 3 1 ECVAM, Institute for Health & Consumer Protection, European Commission Joint Research Centre, 21020 Ispra (VA), Italy; 2 Department of Toxicology, Vrije Universiteit Brussel, Laarbeeklaan 103, 1090 Brussels, Belgium; 3 GlaxoWellcome Research and Development, Park Road, Ware, Hertfordshire SG12 ODP, UK; 4 Unidad de Hepatologia Experimental, Hospital Universitario La Fe, Avda de Campanar 21, 46009 Valencia, Spain; 5 Institut für Toxikologie und Umwelthygiene, Technische Universität München, Lazarettstrasse 62, 80636 Munich, Germany; 6 Preclinical Metabolism and Pharmacokinetics, Sanofi Recherche, Rue du Professeur Blayac 371, 34184 Montpellier Cédex 04, France; 7 School of Biomedical Sciences, University of Nottingham Medical School, Queen’s Medical Centre, Nottingham NG7 2UH, UK; 8 Drug Metabolism and Isotope Chemistry, Bayer, Aprather Weg 18a, 42096 Wuppertal, Germany ATLA 27, 579–638, 1999 579 Summary — In this report, metabolically competent in vitro systems have been reviewed, in the context of drug metabolising enzyme induction. Based on the experience of the scientists involved, a thorough survey of the literature on metabolically competent long-term culture models was performed. Following this, a prevalidation proposal for the use of the collagen gel sandwich hepatocyte culture system for drug metabolising enzyme induction was designed, focusing on the induction of the cytochrome P450 enzymes as the principal enzymes of inter- est. The ultimate goal of this prevalidation proposal is to provide industry and academia with a metabolically competent in vitro alternative for long-term studies. In an initial phase, the prevalidation study will be limited to the investigation of induction. However, proposals for other long-term applications of these systems should be forwarded to the European Centre for the Validation of Alternative Methods for consideration. The prevalidation proposal deals with several issues, including: a) species; b) practical prevalidation methodology; c) enzyme inducers; and d) advantages of working with independent expert laboratories. Since it is preferable to include other alternative tests for drug metabolising enzyme induction, when such tests arise, it is recommended that they meet the same level of development as for the collagen gel sand- wich long-term hepatocyte system. Those tests which do so should begin the prevalidation and validation process. Key words: long-term culture, hepatocytes, drug metabolism, enzyme regulation, induction, cytochrome P450, CYP, collagen gel culture, organotypic culture, co-culture, spheroids. This is the first report of the ECVAM Task Force on Hepatocytes and Metabolically Competent Systems and rep- resents the agreed conclusions of its members as individual scientists. Address for correspondence and reprints: Dr S. Coecke, ECVAM, TP 580, Institute for Health & Consumer Pro- tection, European Commission Joint Research Centre, 21020 Ispra (VA), Italy.