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Environ Toxicol Pharmacol. 2016 Mar;42:190-7. doi: 10.1016/j.etap.2016.01.017. Epub 2016 Jan 27.

QSARs for estimating intrinsic hepatic clearance of organic chemicals in humans.

Author information

1
Radboud University Nijmegen, Institute for Wetland and Water Research, Department of Environmental Science, Heyendaalseweg 135, 6525 AJ Nijmegen, The Netherlands. Electronic address: a.pirovano@science.ru.nl.
2
Helmholtz-Zentrum München - German Research Centre for Environmental Health (GmbH), Research Unit of Molecular Epidemiology, Institute of Epidemiology II, Munich, Germany.
3
Radboud University Nijmegen, Institute for Wetland and Water Research, Department of Environmental Science, Heyendaalseweg 135, 6525 AJ Nijmegen, The Netherlands.
4
Radboud University Nijmegen, Institute for Wetland and Water Research, Department of Environmental Science, Heyendaalseweg 135, 6525 AJ Nijmegen, The Netherlands; Faculty of Management, Science and Technology, Open University, Heerlen, The Netherlands.
5
University of Michigan, School of Public Health, Department of Environmental Health Sciences, 1415 Washington Heights, Ann Arbor, MI, USA.

Abstract

Quantitative structure-activity relationships (QSARs) were developed to predict the in vitro clearance (CLINT) of xenobiotics metabolised in human hepatocytes (118 compounds) and microsomes (115 compounds). Clearance values were gathered from the scientific literature and multiple linear models were built and validated selecting at most 6 predictors from a pool of over 2000 potential molecular descriptors. For the hepatocytes QSAR, the explained variance (Radj(2)) was 67% and the predictive ability (Rext(2)) was 62%. For the microsomes QSAR, Radj(2) was 50% and Rext(2) 30%. For both liver assays, the most important descriptor relates to electronic properties of the compound. Functional groups of fragments were useful to identify specific compounds that have a deviating reaction rate compared to the others, such as polychlorobiphenyls (PCBs) and organic amides which were poorly metabolised by hepatocytes and microsomes, respectively. For hepatocytes, clearance was predominantly determined by electronic characteristics, while size and shape characteristics were less important and partitioning properties were absent. This may suggest that uptake across the membrane and enzyme binding are not rate-limiting steps. Particularly for hepatocytes the QSAR statistics are encouraging, allowing application of the outcomes in in vitro to in vivo extrapolation.

KEYWORDS:

Biotransformation; Clearance (CL(INT)); Hepatocytes; Microsomes; Quantitative structure–activity relationship

PMID:
26874337
DOI:
10.1016/j.etap.2016.01.017
[Indexed for MEDLINE]

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