Oxygen-mediated enhancement of primary hepatocyte metabolism, functional polarization, gene expression, and drug clearance
- 15 September 2009
- journal article
- Published by Proceedings of the National Academy of Sciences in Proceedings of the National Academy of Sciences of the United States of America
- Vol. 106 (37), 15714-15719
- https://doi.org/10.1073/pnas.0906820106
Abstract
The liver is a major site for the metabolism of xenobiotic compounds due to its abundant level of phase I/II metabolic enzymes. With the cost of drug development escalating to over $400 million/drug there is an urgent need for the development of rigorous models of hepatic metabolism for preclinical screening of drug clearance and hepatotoxicity. Here, we present a microenvironment in which primary human and rat hepatocytes maintain a high level of metabolic competence without a long adaptation period. We demonstrate that co-cultures of hepatocytes and endothelial cells in serum-free media seeded under 95% oxygen maintain functional apical and basal polarity, high levels of cytochrome P450 activity, and gene expression profiles on par with freshly isolated hepatocytes. These oxygenated co-cultures demonstrate a remarkable ability to predict in vivo drug clearance rates of both rapid and slow clearing drugs with an R(2) of 0.92. Moreover, as the metabolic function of oxygenated co-cultures stabilizes overnight, preclinical testing can be carried out days or even weeks before other culture methods, significantly reducing associated labor and cost. These results are readily extendable to other culture configurations including three-dimensional culture, bioreactor studies, as well as microfabricated co-cultures.Keywords
This publication has 46 references indexed in Scilit:
- Predicting drug disposition, absorption/elimination/transporter interplay and the role of food on drug absorptionAdvanced Drug Delivery Reviews, 2008
- Liver heparan sulfate proteoglycans mediate clearance of triglyceride-rich lipoproteins independently of LDL receptor family membersJCI Insight, 2007
- Mechanisms of Hepatocyte DetoxificationPublished by Elsevier BV ,2006
- Idiosyncratic drug hepatotoxicityNature Reviews Drug Discovery, 2005
- HETEROTROPIC MODULATION OF SULFOTRANSFERASE 2A1 ACTIVITY BY CELECOXIB: PRODUCT RATIO SWITCHING OF ETHYNYLESTRADIOL SULFATIONDrug Metabolism and Disposition, 2004
- The price of innovation: new estimates of drug development costsJournal of Health Economics, 2003
- Economic Evaluation of Vaccination ProgrammesPharmacoEconomics, 2002
- The Value of Improving the Productivity of the Drug Development ProcessPharmacoEconomics, 2002
- Hepatotoxicity in drug development: detection, significance and solutionsJournal of Hepatology, 1997
- Evaluation of drug interactions in intact hepatocytes: Inhibitors of terfenadine metabolismToxicology in Vitro, 1996