The liver is the most important organ in drug metabolism, and is also the most significantly damaged by drug-induced toxicity. Traditional hepatocyte culture is difficult and is often weakly correlated to clinical endpoints. In order to better understand pharmaceutical liver toxicity and optimize the process of safely bringing a drug through clinical trials and to the patient, we have used a high-throughput 3D culture system to gain in vitro toxicity data, as well as a humanized liver mouse model to gain in vivo toxicity data. The high-throughput 3D culture system, consisting of a complementary micropillar-microwell dual chip design, contains 100 nL cultures in Matrigel, allowing for an efficient use of media and primary human hepatocytes, while also yielding a more biorelevant metabolism profile. The humanized mice are a chimeric system in which the original murine hepatocytes are selectively destroyed and subsequently replaced with primary human hepatocytes. To ensure genetic consistency, the same primary hepatocytes injected into the mice are used for in vitro toxicity studies. These data are mathematically correlated to one another to achieve predictive in vivo responses from in vitro data. We believe these correlations will lead to a greater understanding of the relationship between in vitro and in vivo human toxicity, and to a greater efficiency in pharmaceutical preclinical trials.

In vitro – in vivo liver toxicity correlations of 3D microculture and humanized liver mice

253rd National Meeting (2017)

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