Multiscale modelling approach combining a kinetic model of glutathione metabolism with PBPK models of paracetamol and the potential glutathione-depletion biomarkers ophthalmic acid and 5-oxoproline in humans and rats

Suzanne Geenen; James W. T. Yates; J. Gerry Kenna; Frederic Y. Bois; Ian D. Wilson; Hans V. Westerhoff

doi:10.1039/C3IB20245C

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Corresponding authors

Manchester Centre for Integrative Systems Biology and Doctoral Training Centre ISBML, Manchester Interdisciplinary Biocentre, University of Manchester, 131 Princess Street, Manchester, UK

Drug Metabolism and Pharmacokinetics IM, AstraZeneca, Mereside, Alderley Park, Macclesfield, UK

Oncology iMED DMPK, AstraZeneca, Mereside, Alderley Park, Macclesfield, UK
E-mail: james.yates@astrazeneca.com

Global Safety Assessment, Innovative Medicines, AstraZeneca R&D, Alderley Park, Macclesfield, UK

Chair of Mathematical Modeling for Systems Toxicology, Université de Technologie de Compiègne, Royallieu Research Center, 60200 Compiegne, France

INERIS, 60550 Verneuil-en-Halatte, France

Dept of Surgery and Cancer, Sir Alexander Fleming Building, Imperial College, Exhibition Rd, South Kensington, London, UK

Molecular Cell Physiology, VU University, Amsterdam, The Netherlands

Systems and Synthetic Biology, FNWI, Universiteit van Amsterdam, The Netherlands

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A key role of the antioxidant glutathione is detoxification of chemically reactive electrophilic drug metabolites within the liver. Therefore glutathione depletion can have severe toxic consequences. Ophthalmic acid and 5-oxoproline are metabolites involved in glutathione metabolism, which can be measured readily in the blood and urine and have been proposed as candidate biomarkers of hepatic glutathione content. However, currently it is unclear whether their concentrations in plasma exhibit a robust correlation with hepatic glutathione content. To explore this important question, we have developed a novel approach which combines a physiologically based pharmacokinetic (PBPK) model of metabolism and disposition of paracetamol (acetaminophen) with a previously developed mathematical systems model of hepatic glutathione homeostasis. Paracetamol is metabolised to reactive intermediates which deplete glutathione and cause toxicity when given at high doses. Our model correctly predicted that hepatic glutathione depletion following paracetamol administration resulted in elevated concentrations of 5-oxoproline and ophthalmic acid in blood and of 5-oxoproline in urine. However, we also found from the model that concentrations of both of the compounds were likely to be influenced by prolonged administration of paracetamol and by the concentrations of intracellular metabolites such as methionine. We conclude that care must be taken when extrapolating from concentrations of these biomarkers to hepatic glutathione status.

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Suzanne Geenen
James W. T. Yates
J. Gerry Kenna
Frederic Y. Bois
Ian D. Wilson
Hans V. Westerhoff

Integrative Biology