University of Oulu

Varvara Gouliarmou, Alfonso Maria Lostia, Sandra Coecke, Camilla Bernasconi, Jos Bessems, Jean Lou Dorne, Stephen Ferguson, Emanuela Testai, Ursula Gundert Remy, J. Brian Houston, Mario Monshouwer, Andy Nong, Olavi Pelkonen, Siegfried Morath, Barbara A. Wetmore, Andrew Worth, Ugo Zanelli, Maria Chiara Zorzoli, Maurice Whelan, Establishing a systematic framework to characterise in vitro methods for human hepatic metabolic clearance, Toxicology in Vitro, Volume 53, 2018, Pages 233-244, ISSN 0887-2333,

Establishing a systematic framework to characterise in vitro methods for human hepatic metabolic clearance

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Author: Gouliarmou, Varvara1; Lostia, Alfonso Maria1; Coecke, Sandra1;
Organizations: 1European Commission, Joint Research Centre (JRC), Via Enrico Fermi 2749, 21027 Ispra, VA, Italy
2Present address: VITO (Flemish Institute of Technological Research), Mol, Belgium
3European Food Safety Authority, Via Carlo Magno, 1A, 43126 Parma, PR, Italy
4US National Toxicology Program, National Institute of Environmental Health Sciences, Durham, NC 27709, USA
5Istituto Superiore di Sanità, Environment & Health Dept., Viale Regina Elena 299, 00161 Rome, Italy
6Institute for Clinical Pharmacology and Toxicology, Charité, Universitätsmedizin Berlin, Charitéplatz 1, D-110117 Berlin, Germany
7Manchester Pharmacy School, University of Manchester, Manchester M13 9PT, UK
8Janssen Research & Development, Turnhoutseweg 30, 2340 Beerse, Belgium
9Computational Toxicology Laboratory, Exposure and Biomonitoring Division, Health Canada - Environmental Health Science and Research Bureau, 50 Colombine Dwy, Environmental Health Centre, Tunney's Pasture AL:0800C, Ottawa, ON K1A 0K9, Canada
10Research Unit of Biomedicine/Pharmacology and Toxicology, Faculty of Medicine, Aapistie 5 B, FIN-90014, University of Oulu, Finland
11U.S. EPA, Office of Research and Development, National Exposure Research Laboratory, 109 T.W. Alexander Drive, MD E243-04, Research Triangle Park, NC 27711, USA
12Discovery DMPK, Merck KGaA Darmstadt, Germany
Format: article
Version: accepted version
Access: open
Online Access: PDF Full Text (PDF, 1.2 MB)
Persistent link:
Language: English
Published: Elsevier, 2018
Publish Date: 2019-08-09


Hepatic metabolic clearance is one of the most important factors driving the overall kinetics of chemicals including substances used in various product categories such as pesticides, biocides, pharmaceuticals, and cosmetics. A large number of in vitro systems from purified isozymes and subcellular organelles to hepatocytes in simple cultures and in complex scaffold setups are available for measuring hepatic metabolic clearance for different applications. However, there is currently no approach for systematically characterising and comparing these in vitro methods in terms of their design, applicability and performance. To address this, existing knowledge in the field of in vitro human hepatic metabolic clearance methods was gathered and analysed in order to establish a framework to systematically characterise methods based on a set of relevant components. An analogous framework would be also applicable for non-human in vitro systems. The components are associated with the biological test systems used (e.g. subcellular or cells), the in vitro method (e.g. number of cells, test item solubility), related analytical techniques, data interpretation methods (based on substrate depletion/metabolite formation), and performance assessments (precision and accuracy of clearance measurements). To facilitate the regulatory acceptance of this class of methods, it is intended that the framework provide the basis of harmonisation work within the OECD.

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Series: Toxicology in vitro
ISSN: 0887-2333
ISSN-E: 1879-3177
ISSN-L: 0887-2333
Volume: 53
Pages: 233 - 244
DOI: 10.1016/j.tiv.2018.08.004
Type of Publication: A1 Journal article – refereed
Field of Science: 317 Pharmacy
Copyright information: © 2018. This manuscript version is made available under the CC-BY-NC-ND 4.0 license