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Establishing a systematic framework to characterise in vitro methods for human hepatic metabolic clearance
Citation:
Gouliarmou, V., A. Lostia, S. Coecke, C. Bernasconi, J. Bessems, J. Dorne, S. Ferguson, E. Testai, U. Remy, J. Houston, M. Monshouwer, A. Nong, O. Pelkonen, S. Morath, B. Wetmore, A. Worth, U. Zanelli, M. Zorzoli, AND M. Whelan. Establishing a systematic framework to characterise in vitro methods for human hepatic metabolic clearance. TOXICOLOGY IN VITRO. Elsevier Science Ltd, New York, NY, 53:233-244, (2018). https://doi.org/10.1016/j.tiv.2018.08.004
Impact/Purpose:
21st century toxicity testing approaches are designed to utilize human cell-based approaches as an alternative to the traditional use of high dose animal toxicology studies to assess chemical toxicity. By employing human cell systems and screening across a wide range of concentrations, information regarding biological perturbations monitored in these assays can be used to assess the likelihood and the potency of a particular effect occurring given a chemical exposure. To relate these in vitro tested concentrations to an external exposure estimate required to achieve these effects, an understanding of hepatic metabolic clearance is required to adequately consider chemical toxicokinetics. Numerous methods have been used over the past four decades to assess hepatic clearance; however, to date no concerted effort has been made to characterize a methodological framework that will ensure consistency and reproducibility of such metabolic clearance data generation across studies. This manuscript is an outcome from a workshop that convened experts in toxicokinetics, pharmacokinetics, risk assessment, liver cell biology and physiologically-based pharmacokinetic modeling to review the existing methods and to provide recommendations for the development of such a framework.
Description:
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.
URLs/Downloads:
DOI: Establishing a systematic framework to characterise in vitro methods for human hepatic metabolic clearance