PhysioMimix : Drug Discovery Applications

  • Metabolite Profiling and Pharmacokinetic Evaluation of Hydrocortisone in a Perfused Three-Dimensional Human Liver Bioreactor

    Inflammation of the liver may result from infection, autoimmune disorders, alcohol abuse, or fat accumulation (Adams et al., 2010). Severe inflammation can be life-threatening, whereas mild inflammation can change drug metabolism profiles (Adams et al., 2010) and may play a role in liver injury (Park et al., 2004; Deng et al., 2009). Drug-induced liver injury has resulted in late-stage clinical trial failures and postmarket withdrawals (Guengerich, 2011). A postulated mechanism for toxicity involves leakage of bacterial products from the gut to the liver, causing inflammation-related susceptibility to liver injury (Deng et al., 2008). This has been demonstrated in animal models (Roth et al., 2003; Deng et al., 2009; Roth and Ganey, 2010) but could be supported by a human-derived in vitro model that recapitulates the response of liver to inflammation. The simplest model is the two-dimensional culture of primary hepatocytes, either as a monolayer or overlaid with extracellular matrix components in multiwall plates…

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  • Quantitative Assessment of Population Variability in Hepatic Drug Metabolism Using a Perfused Three-Dimensional Human Liver Microphysiological Systems

    In this work, we first describe the population variability in hepatic drug metabolism using cryopreserved hepatocytes from five different donors cultured in a perfused three-dimensional human liver microphysiological system, and then show how the resulting data can be integrated with a modelling and simulation framework to accomplish in vitro–in vivo translation. For each donor, metabolic depletion profiles of six compounds (phenacetin, diclofenac, lidocaine, ibuprofen, propranolol, and prednisolone)were measured, along with metabolite formation, mRNA levels of 90 metabolism-related genes, and markers of functional viability [lactate dehydrogenase (LDH) release, albumin, and ureaproduction]. Drug depletion data were analyzed with mixed-effects modelling. Substantial inter-donor variability was observed with respect to gene expression levels, drug metabolism, and other measured hepatocyte functions…

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