Towards better models and mechanistic biomarkers for drug-induced gastrointestinal injury

Daniel F Carr; Seyoum Ayehunie; Andrea Davies; Carrie A Duckworth; Stephanie French; Neil Hall; Syed Hussain; Howard R Mellor; Alan Norris; B Kevin Park; Alexander Penrose; D Mark Pritchard; Chris S Probert; Shashi Ramaiah; Claire Sadler; Michael Schmitt; Alison Shaw; James E Sidaway; Robert G Vries; Matthew Wagoner; Munir Pirmohamed

doi:10.1016/j.pharmthera.2017.01.002

Towards better models and mechanistic biomarkers for drug-induced gastrointestinal injury

Pharmacol Ther. 2017 Apr:172:181-194. doi: 10.1016/j.pharmthera.2017.01.002. Epub 2017 Jan 27.

Authors

Daniel F Carr¹, Seyoum Ayehunie², Andrea Davies³, Carrie A Duckworth⁴, Stephanie French³, Neil Hall⁵, Syed Hussain⁶, Howard R Mellor⁷, Alan Norris³, B Kevin Park³, Alexander Penrose³, D Mark Pritchard⁴, Chris S Probert⁴, Shashi Ramaiah⁸, Claire Sadler⁹, Michael Schmitt¹⁰, Alison Shaw¹¹, James E Sidaway¹², Robert G Vries¹³, Matthew Wagoner¹⁴, Munir Pirmohamed³

Affiliations

¹ MRC Centre for Drug Safety Science, Department of Clinical and Molecular Pharmacology, Institute of Translational Medicine, University of Liverpool, Liverpool, UK. Electronic address: d.carr@liverpool.ac.uk.
² MatTek Corporation, Ashland, MA, USA.
³ MRC Centre for Drug Safety Science, Department of Clinical and Molecular Pharmacology, Institute of Translational Medicine, University of Liverpool, Liverpool, UK.
⁴ Department of Cellular and Molecular Physiology, Institute of Translational Medicine, University of Liverpool, Liverpool L69 3GE, UK.
⁵ Department of Comparative and Functional Genomics, Institute of Integrative Biology, University of Liverpool, Liverpool L69 7ZB, UK.
⁶ Department of Molecular and Clinical Cancer Medicine Institute of Translational Medicine, University of Liverpool, Liverpool L69 3GA, UK.
⁷ Vertex Pharmaceuticals (Europe), Abingdon, Oxfordshire, UK.
⁸ Pfizer Inc, Cambridge, MA, USA.
⁹ ApconiX, Alderley Edge, Cheshire, UK.
¹⁰ Merck KGaA, Darmstadt, Germany.
¹¹ Medicines & Healthcare Products Regulatory Agency, London, UK.
¹² Phenotox Ltd, Bollington, Cheshire, UK.
¹³ Hubrecht Organoid Technology, Utrecht, The Netherlands.
¹⁴ AstraZeneca Pharmaceuticals, Innovative Medicines and Early Development, Drug Safety and Metabolism, Waltham, MA, United States.

PMID: 28132905
DOI: 10.1016/j.pharmthera.2017.01.002

Abstract

Adverse drug reactions affecting the gastrointestinal (GI) tract are a serious burden on patients, healthcare providers and the pharmaceutical industry. GI toxicity encompasses a range of pathologies in different parts of the GI tract. However, to date no specific mechanistic diagnostic/prognostic biomarkers or translatable pre-clinical models of GI toxicity exist. This review will cover the current knowledge of GI ADRs, existing biomarkers and models with potential application for toxicity screening/monitoring. We focus on the current gaps in our knowledge, the potential opportunities and recommend that a systematic approach is needed to identify mechanism-based GI biomarkers with potential for clinical translation.

Keywords: Adverse drug reaction; Biomarker; Gastrointestinal; In vitro; In vivo; Toxicity.

Publication types

Review

MeSH terms

Animals
Biomarkers / metabolism
Drug Design
Drug Discovery / methods
Drug Evaluation, Preclinical / methods
Drug-Related Side Effects and Adverse Reactions / diagnosis*
Gastrointestinal Diseases / chemically induced*
Gastrointestinal Diseases / physiopathology
Humans
Models, Biological*
Toxicity Tests / methods

Substances

Biomarkers

Grants and funding

MR/L006758/1/MRC_/Medical Research Council/United Kingdom