Science Pool

Reducing the sample cycle time for LC-MS analysis is critical in increasing throughput and improving efficiency.

In this poster, we focus on:

• the development of a ultra-fast chromatography method with rapid cycle time
• the analysis of the sensitivity, linearity, reproducibility, robustness and matrix effects for the method
• applicability to intrinsic clearance determination

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TAK-875 (fasiglifam) is a GPR40 agonist which was developed for the treatment of type 2 diabetes. However, TAK-875 was withdrawn from phase III clinical trials due to drug-induced liver injury (DILI).

In this poster, we focus on:

• investigating the mechanism behind the hepatotoxicity of TAK-875
• an in-depth understanding of the effect of TAK-875 on mitochondrial toxicity 
• understanding the impact of plasma protein binding

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In order to accurately predict human pharmacokinetics and efficacious dose, a robust measurements of clearance is essential.

In this poster, we focus on:

• a novel primary human hepatocyte media supplement (HepExtend^TM)
• a comparison of HepExtend^TM with the widely used CM4000 with and without a Geltrex overlay
• a correlation of scaled in vitro human intrinsic clearance with in vivo human intrinsic clearance

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Advances in human iPSC-derived neuronal models in conjunction with microelectrode array (MEA) technology has enhanced our understanding of complex burst organisation and network characteristics in humans. This now provides a viable human model for studying drug-induced toxicity and CNS liabilities as well as potential pharmacology effects on the neurones.

In this poster, we focus on:

• investigating co-cultures of human iPSC-derived glutamatergic neurons with astrocytes on the MEA platform
• determining spike activity, burst organisation and network organisation (synchrony) patterns for different types of CNS compounds (GABA_A agonists, potassium channel blockers, opioid receptor agonist, glycine receptor antagonist and cholinergic and muscarinic receptor agonists)
• understanding developmental and pharmacological responses when assessed by MEA

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Drug or chemical-induced nephrotoxicity is responsible for 25% of renal failure in the clinic.

In this poster, we focus on:

• a comparison of 2D and 3D human primary kidney cell-based models for predicting nephrotoxicity
• the use of mono and co-culture kidney models
• using HCS for the simultaneous detection of DNA structure, GSH content, mitochondrial toxicity and phospholipidosis

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Pilocarpine is a muscarinic receptor agonist which is used as a model inducer of epilepsy in the rat. We evaluated the seizurogenic response of pilocarpine using an in vitro MEA platform.

In this poster, we focus on:

• a comparison of pilocarpine response in different neuronal cell types; cryopreserved rat cortical neurons, cryopreserved rat hippocampal neurons and a co-culture of human iPSC-derived glutamatergic neurons with astrocytes
• the impact of DIV and cell maturation on the response
• identifying muscarinic receptor expression over time

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The benefits of 3D cell-based models in the prediction of drug-induced liver injury are now being realised. 

In this poster, we focus on:

• the use of 3D models (cryopreserved human hepatocytes co-cultured with human non-parenchymal cells compared with HepaRG monocultures)
• cytochrome P450 (CYP) activity in the different models
• HCS analysis of DNA structure, GSH content, ROS formation and mitochondrial function
• prediction of DILI potential for a set of DILI-positive and negative compounds

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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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