title: Novelin vitroand mathematical models for the prediction of chemical toxicity.
abstract: The focus of much scientific and medical research is directed towards understanding the disease process and defining therapeutic intervention strategies. The scientific basis of drug safety is very complex and currently remains poorly understood, despite the fact that adverse drug reactions (ADRs) are a major health concern and a serious impediment to development of new medicines. Toxicity issues account for ∼21% drug attrition during drug development and safety testing strategies require considerable animal use. Mechanistic relationships between drug plasma levels and molecular/cellular events that culminate in whole organ toxicity underpins development of novel safety assessment strategies. Currentin vitrotest systems are poorly predictive of toxicity of chemicals entering the systemic circulation, particularly to the liver. Such systems fall short because of (1) the physiological gap between cells currently used and human hepatocytes existing in their native state, (2) the lack of physiological integration with other cells/systems within organs, required to amplify the initial toxicological lesion into overt toxicity, (3) the inability to assess how low level cell damage induced by chemicals may develop into overt organ toxicity in a minority of patients, (4) lack of consideration of systemic effects. Reproduction of centrilobular and periportal hepatocyte phenotypes inin vitroculture is crucial for sensitive detection of cellular stress. Hepatocyte metabolism/phenotype is dependent on cell position along the liver lobule, with corresponding differences in exposure to substrate, oxygen and hormone gradients. Application of bioartificial liver (BAL) technology can encompassin vitropredictive toxicity testing with enhanced sensitivity and improved mechanistic understanding. Combining this technology with mechanistic mathematical models describing intracellular metabolism, fluid-flow, substrate, hormone and nutrient distribution provides the opportunity to design the BAL specifically to mimic thein vivoscenario. Such mathematical models enable theoretical hypothesis testing, will inform the design ofin vitroexperiments, and will enable both refinement and reduction ofin vivoanimal trials. In this way, development of novel mathematical modelling tools will help to focus and directin vitroandin vivoresearch, and can be used as a framework for other areas of drug safety science.
authors.affiliation: MRC Centre for Drug Safety Science , Department of Molecular and Clinical Pharmacology , Institute of Translational Medicine , The University of Liverpool , Sherrington Building , Ashton St. , Liverpool , L69 3GE , UK . Email: dom@liv.ac.uk ; ; Tel: +44 (0)151 794 5791.
authors.forename: Dominic P
authors.initials: DP
authors.lastname: Williams
authors.affiliation: Department of Mechanical Engineering , University College London , Torrington Place , London WC1E 7JE , UK.
authors.forename: Rebecca
authors.initials: R
authors.lastname: Shipley
authors.affiliation: Department of Chemical Engineering , University of Bath , Claverton Down , Bath , BA2 7AY , UK.
authors.forename: Marianne J
authors.initials: MJ
authors.lastname: Ellis
authors.affiliation: Department of Mathematics and Statistics , University of Strathclyde , Livingstone Tower , 26 Richmond Street , Glasgow , G1 1XH , UK.
authors.forename: Steve
authors.initials: S
authors.lastname: Webb
authors.affiliation: School of Mathematical Sciences , Loughborough University , Loughborough , LE11 3TU , UK.
authors.forename: John
authors.initials: J
authors.lastname: Ward
authors.affiliation: Simcyp Limited , Blades Enterprise Centre , John Street , Sheffield S2 4SU , UK.
authors.forename: Iain
authors.initials: I
authors.lastname: Gardner
authors.affiliation: NC3Rs Gibbs Building , 215 Euston Road , London , NW1 2BE , UK.
authors.forename: Stuart
authors.initials: S
authors.lastname: Creton