%0 Journal Article
%T Quantitative Evaluation of Cytochrome P450 3A4 Inhibition and Hepatotoxicity in HepaRG 3
%A Dae-Seop Shin
%A Hyewon Seo
%A Jeongmin Joo
%A Jung Yoon Yang
%A Myung Ae Bae
%A Sang Kyum Kim
%A Seong Soon Kim
%A So Hee Im
%J International Journal of Toxicology
%@ 1092-874X
%D 2018
%R 10.1177/1091581818780149
%X Predicting drug¨Cdrug interactions (DDIs) is an important step during drug development to avoid unexpected side effects. Cytochrome P450 (CYP) 3A4 is the most abundant human hepatic phase I enzyme, which metabolizes >50% of therapeutic drugs. Therefore, it is essential to test the potential of a drug candidate to induce CYP3A4 expression or inhibit its activity. Recently, 3-dimensional (3-D) mammalian cell culture models have been adopted in drug discovery research to assess toxicity, DDIs, and pharmacokinetics. In this study, we applied a human 3-D spheroid culture protocol using HepaRG cells combined with liquid chromatography-tandem mass spectrometry (LC-MS/MS) to assess its ability to predict CYP3A4 inhibition. Levels of midazolam, a specific substrate of CYP3A4, were used to determine the long-term metabolic capacity of CYP3A4. Midazolam was decreased in the 3-D HepaRG culture system by ¡«80% over 7 days, whereas its primary metabolite, 1-hydroxymidazolam, increased by ¡«40%. Next, we assessed hepatotoxicity by determining the cytotoxicity of known hepatotoxicants in HepaRG spheroids, HepG2 cells, and primary human hepatocytes. Significant differences in cytotoxicity were detected in the system using 3-D HepaRG spheroids. These results suggest that 3-D HepaRG spheroids are a good model for prediction of CYP inhibition and hepatotoxicity in screening of early drug candidates
%K hepatotoxicity
%K CYP3A4
%K 3-D HepaRG spheroid
%U https://journals.sagepub.com/doi/full/10.1177/1091581818780149