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HepatoPac™ Cultures: Low Clearance and Metabolite Identification Application Utility of Micro-patterned Co-cultures for Drug Toxicity Studies.

Abstract: Investigation of metabolite formation in preclinical species is an important step for understanding the efficacy and safety of candidate drug molecules. Typically, in vitro systems (liver microsomes or monocultured hepatocytes) are used to identify and compare metabolites among human and animal species before selection of preclinical species for pharmacokinetic, toxicological and toxicokinetic studies. However, metabolites formed in vitro often do not correlate with in vivo results. Moreover, metabolites that are unique or disproportionately higher in humans require additional safety testing; thus, in vitro systems that offer potentially better up-front predictivity relative to human metabolism provide a likely basis for risk mitigation and improved efficiency in the product development process. We will present results evaluating metabolite generation and compound stability using HepatoPac™, a novel micropatterned hepatocyte co-culture system, which has the capability to support long duration incubations of test articles without replacement of culture medium. Several compounds were tested using human, rat and monkey HepatoPac™ culture systems. The metabolites were characterized and profiles were compared with profiles of circulating metabolites observed in human, rat, and monkey. The ability of HepatoPac™ systems to generate relevant in vivo metabolites was compared with that of traditional hepatocyte suspension cultures.

 

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