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MSc by Research Programme: Assessment of plated cryopreserved hepatocytes as a tool to accurately determine the intrinsic clearance of low metabolism compounds


School of Life Sciences

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Dr K Read No more applications being accepted Self-Funded PhD Students Only

About the Project

This course allows you to work alongside our world renowned experts from the School of Life Sciences and gain a ’real research’ experience. You will have the opportunity to select a research project from a variety of thematic areas of research.

You will be part of our collaborative working environment and have access to outstanding shared facilities such as microscopy and proteomics. Throughout your year, you will develop an advanced level of knowledge on your topic of interest as well as the ability to perform independent research in the topic area. Alongside basic science training in experimental design, data handling and research ethics, we will help you to develop skills in critical assessment and communication. This will be supported by workshops in scientific writing, presentation skills, ethics, laboratory safety, statistics, public engagement and optional applied bioinformatics.

The period of study is one year full-time or two years part-time research, which includes two months to write up the thesis. Please apply via the UCAS postgraduate application form: https://digital.ucas.com/courses/details?coursePrimaryId=c735d826-42b6-ca1f-50db-2a3ac6f68718

Reducing the metabolic clearance of new chemical entities is important in drug discovery projects helping to reduce dose, improve exposure and prolong the half-life of new chemical entities (NCE’s). Primary hepatocytes in suspension are routinely used to assess intrinsic clearance and predict in vivo clearance, however incubation times are limited to <4 hours, which is not long enough to accurately determine the metabolic stability of slowly metabolised compounds. It is important to be able to generate accurate in vitro intrinsic clearance when predicting in vivo human clearance so an alternative assay is necessary for slow/poorly metabolised NCE’s.
Plateable ‘metabolism qualified’ cryopreserved human hepatocytes are a cost-effective, commercially available in vitro tool that maintain in vivo-like enzyme expression levels and cell morphology. These cells can be cultured for more prolonged timescales and a more accurate evaluation of metabolic stability can be determined. Plateable human hepatocytes have previously been demonstrated to predict well with observed in vivo human hepatic clearance to within 3-fold in 78% of the compounds tested. Differing culture media and supplements have also shown to have a significant effect upon culture time and metabolic enzyme activity over the course of the experiment thereby improving the precision of human in vivo predictions.

Proof-of-concept will initially be performed on a test set of low intrinsic clearance compounds with available in vivo clearance data. A variety of experimental conditions will be explored to validate this as an accurate tool for delivering better prediction of slow/low intrinsic clearance NCE’s within the Drug Discovery Unit.
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