ADME/Tox


Advanced Cell Diagnostics Pharma Assay Services


Improvements to hepatocyte cultures As pharmaceutical companies make significant strides towards developing compounds that are increasingly stable, there is a need for the hepato- cyte metabolic capacity to be stable enough to detect relevant metabolism over longer terms. The sandwich culture model has become an invaluable tool and a common in vitro model to investigate drug-drug interactions due to their ability to main- tain many of the structural features of the in vivo hepatocytes. While enabling query of the more rel- evant hepatocyte features such as polarity and appropriate drug transport kinetics, the sandwich culture format does not completely solve the tech- nical issue of metabolic decline. There have, however, been advances in other 3D culture methods that are gaining popularity in use. Spheroids are spherical cultures that can be pro- duced by either embedding hepatocytes in non- adhesive hydrogels or allowing hepatocytes to self- assemble in low attachment cell culture plates or hanging drops. Studies have shown that the forma- tion of multicellular hepatocyte spheroids in the 3D culture is a promising approach for enhancing liver specific functions. Hepatocytes cultures in spheroids resemble polarised cell structures and direct cell-cell contact and importantly can main- tain steady metabolic function for more than 14 days. This approach also enables the self-assembly of multiple cell types in the liver creating a pseudo microtissue much more similar to the in vivo hep- atocyte environment.


Another method shown to improve hepatocyte health and metabolic stability are fluidic flow sys- tem whereby cells in a monolayer are placed in chambers with media flowing and recirculating. While they may not be as amenable to higher throughput applications as spheroids, flow-based cell culture systems also stabilise metabolic activity for more than 14 days with the added benefit of allowing longer-term hepatocyte cultures without frequent media changes. Without frequent media changes, metabolites generated from slowly metabolised drugs are allowed to build up in the culture improving chances of detecting the metabolite during bio-analysis.


Importance of advanced culture formats in hepatotoxicity With respect to hepatotoxicity, damage to hepato- cytes is often secondary to immune responses or other endocrine and paracrine signalling. The com- plex signalling between cells and tissues during a toxic response to drugs and chemicals has implica- tions in how well an in vitro liver model needs to


Drug Discovery World Summer 2017


Comprehensive tissue-based gene expression analysis services.


including detection of alternative splice variants and viral-vector expressed RNAs


• Any tissueall standard tissue preparations ae accepted inclding achival tissues, TMAs, frozen tissue and cell preps


• Tissue sourcingreliable sources for human and animal tissues


 pathologist review • Quantitative image analysis HALO™ Software • 9,000+ catalog targets available • Two weeks for new probe design


• Four weeks turn-around time from receipt of samples to results for typical projects Extensive Experience


•10,000+ slides analyzed per year • 500+ tagetspecific tisse epession assays validated and successfully performed


• 150+ tissue types including normal human, preclinical animals, clinical specimens, humanized mouse and syngeneic mouse tumor models


• Eight automated staining systems from Leica Biosystems and Ventana Medical Systems


Introducing BaseScope™ Assays


• Detect and visualize diverse RNA targets including splice variants, homologous sequences, CAR-T cell clones and more, all within the cellular morphological context


Learn more at acdbio.com/pas


For Research Use Only. Not for diagnostic use. RNAscope is a registered trademark of Advanced Cell Diagnostics, Inc. in the United States or other countries. All rights reserved. ©2016 Advanced Cell Diagnostics, Inc.


Page 1  |  Page 2  |  Page 3  |  Page 4  |  Page 5  |  Page 6  |  Page 7  |  Page 8  |  Page 9  |  Page 10  |  Page 11  |  Page 12  |  Page 13  |  Page 14  |  Page 15  |  Page 16  |  Page 17  |  Page 18  |  Page 19  |  Page 20  |  Page 21  |  Page 22  |  Page 23  |  Page 24  |  Page 25  |  Page 26  |  Page 27  |  Page 28  |  Page 29  |  Page 30  |  Page 31  |  Page 32  |  Page 33  |  Page 34  |  Page 35  |  Page 36  |  Page 37  |  Page 38  |  Page 39  |  Page 40  |  Page 41  |  Page 42  |  Page 43  |  Page 44  |  Page 45  |  Page 46  |  Page 47  |  Page 48  |  Page 49  |  Page 50  |  Page 51  |  Page 52  |  Page 53  |  Page 54  |  Page 55  |  Page 56  |  Page 57  |  Page 58  |  Page 59  |  Page 60  |  Page 61  |  Page 62  |  Page 63  |  Page 64  |  Page 65  |  Page 66  |  Page 67  |  Page 68  |  Page 69  |  Page 70  |  Page 71  |  Page 72