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Towards harmonization of test methods for in vitro hepatic clearance studies
Jochem Louisse1, Martin Alewijn1, Ad A C M Peijnenburg1
1Wageningen Food Safety Research (WFSR), part of Wageningen University and Research, Wageningen, the Netherlands.
Summary
Non-animal toxicokinetic studies, like in vitro hepatic clearance, are vital for chemical risk assessment. Key experimental factors influencing intrinsic clearance (CLint) values include hepatocyte concentration, species, and culture medium.
Area of Science:
- Toxicology
- Pharmacokinetics
- In vitro toxicology
Background:
- Non-animal methods, specifically in vitro hepatic metabolic clearance studies, are essential for chemical risk evaluations.
- Regulatory acceptance of in vitro clearance data necessitates the development of standardized test guidelines.
- Understanding factors influencing in vitro clearance is critical for reliable toxicokinetic assessments.
Purpose of the Study:
- To investigate experimental conditions affecting intrinsic clearance (CLint) values in in vitro hepatic clearance studies.
- To identify key methodological factors that impact the variability of obtained CLint values.
Main Methods:
- Collected in vitro hepatic CLint data from 42 published studies (1995-2018) using rat or human hepatocytes.
- Analyzed methodological aspects of the experiments alongside CLint values.
- Employed random forest regression analysis to estimate the systematic effects of experimental variables on CLint.
Main Results:
- CLint values for most chemicals varied by over an order of magnitude across studies.
- Hepatocyte concentration, species (rat vs. human), and culture medium were identified as the most impactful factors on CLint.
- Calculating unbound intrinsic clearance (CLint,u) marginally reduced data variation.
Conclusions:
- Experimental conditions significantly influence in vitro hepatic CLint values, contributing to data variability.
- A harmonized protocol should aim for conditions that yield relatively high in vitro CLint values to better predict in vivo clearance, which is often underpredicted.
- Standardizing factors like hepatocyte concentration, species, and medium is crucial for regulatory acceptance of non-animal toxicokinetic data.
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