Science Pool

Drug-induced liver injury (often termed DILI) is a major cause of drug failure. The aetiology of DILI is often complex and multifactorial - meaning a single endpoint is unlikely to be sufficient in predicting this liability. Although 2D DILI models have traditionally been used in he prediction of DILI, the advantages of 3D models are now being realised.

In this poster, we focus on:

• the use of multiparametric confocal high content screening (HCS) in DILI prediction
• comparison of co-cultures of human liver 3D microtissues containing cryopreserved human hepatocytes with human non-parenchymal cells and HepaRG 3D spheroids
• the assessment of a set of DILI-positive and DILI-negative compounds following drug exposure over 14 days
• endpoints for DNA structure, GSH content, ROS formation and mitochondrial function

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Real time mass defect filtering (MDF) on independent acquisition (IDA) scans enable the generation of simultaneous selective MS and MSMS data in one injection.

In this poster, we focus on:

• the use of high resolution mass spectrometry and mass defect filtering combined with rapid chromatographic run times and semi-automated commercial software for soft-spot identification of metabolites
• demonstration of the metabolite soft-spot method using verapamil and dextromethorphan

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Drug-induced mitochondrial toxicity has been implicated in adverse events such as liver failure and cardiotoxicity. There are several in vitro assays used to detect mitochondrial toxicity including the glu/gal cytotoxicity assay, high content screening for mitochondrial membrane potential and the Seahorse flux analyser to detect OCR (cellular oxygen consumption rate), reserve capacity and ECAR (extracellular acidification rate).

In this poster, we focus on:

• an analysis of the different methods for detecting mitochondrial toxicity
• an insight into the mechanism of mitochondrial toxicity using the permeabilised cell assay. 

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Domoic acid is a neurotoxin which was associated with the poisoning of 107 people and 3 subsequent deaths on Prince Edward Island in 1987 following the ingestion of mussels containing this poison. The associated neurotoxic effects of domoic acid are clearly identified at concentrations of ≥ 1µM using neurons analysed on a microelectrode array (MEA) platform. Interestingly, domoic acid had no effect up to 25µM in the neurite outgrowth assay (another common method for detecting neurotoxicity).

In this poster, we focus on:

• a comparison of the neurite outgrowth assay with the MEA platform
• sensitivity of the two methods for detecting neurotoxins and seizurogenic compounds
• a screening strategy for testing neurotoxic compounds 

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Pilocarpine is a muscarinic receptor agonist, originally developed to treat dry mouth and glaucoma. It is also used to induce epilepsy in the rat. 

In this poster, we focus on:

• pilocarpine response in vitro using MEA
• analysis of the neuronal responses of different cell types such as cryopreserved rat cortical neurons, rat hippocampal neurons and human iPSC-derived glutamatergic neurons and astrocytes
• the impact of cell maturation (DIV)

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Microelectrode array (MEA) is a powerful technique for the prediction of proarrhythmic liability. One of the main advantages of MEA is its ability to predict unexpected cardiac liabilities and long term chronic effects in vitro. 

In this poster, we focus on:

• the ability of the MEA platform to predict chronic long term effects including hERG trafficking
• predicting the cardiotoxicity of BMS-986094 (INX-08189), a hepatitis C therapy which caused death in its clinical trial after multiple weeks

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Pre-incubating with inhibitor can influence inhibitory potency for some drug transporters such as OATP1B1. It is thought that this phenomenon is a consequence of the time taken for some inhibitors to accumulate inside the cell.

In this poster, we focus on:

• a comparison of a 30 min pre-incubation time with a 15 min pre-incubation time for OATP1B1
• the impact of inhibitor pre-incubation on P-gp and BCRP inhibition in a polarised cell monolayer

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The mitochondria are a common target of drug-induced toxicity. A number of approaches are used to detect mitochondrial toxicity but how do we know which to use?

In this poster, we focus on:

• a comparison of the different methods including the glucose/galactose (glu/gal) cytotoxicity assay, high content screening (HCS) method for mitochondrial membrane potential and cytotoxicity, and the Seahorse flux analyser
• the ability of the different methods to predict mitochondrial toxicity through sensitivity, specificity and accuracy assessment
• an insight into the mechanism of mitochondrial toxicity through the Seahorse flux analyser and permeabilised cell assay.

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Cardiac left ventricular hypertrophy is a risk factor for heart failure. Morphological (structural) effects such as cardiac hypertrophy can be drug-induced therefore it is important to identify these liabilities at an early stage of drug discovery and development.

In this poster, we focus on:

• using HCS to detect cardiac hypertrophy
• the comparison of single cell, co-culture and triculture microtissues models for predicting cardiac hypertrophy

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Incubation times for in vitro hepatocyte stability assays are usually relatively short in order to maintain cell viability and enzymatic activity. This can limit the accuracy of clearance prediction for stable compounds. 

In this poster, we focus on:

• a comparison of three human models of in vitro clearance; the HμREL coculture model, 2D hepatocyte monoculture model and suspension hepatocyte model 
• data were scaled to predict in vivo human clearance
• the suitability of each system to accurately predict the clearance of stable compounds was assessed

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