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Predicting drug-induced liver injury is still a big challenge for the research and development of pharmaceuticals. Primary human hepatocytes (PHH) are the gold standard cell sources for examining drug metabolism, drug-drug interaction (DDI) and hepatotoxicity in humans in vitro. However, their supply does not meet the demand of laboratories sufficiently, and only a limited number of lots of PHH are commercially available. Recently, human iPS cell-derived hepatocytes have been reported and are anticipated to be used as an alternative to PHH. However, drug metabolizing activities of these human iPS-derived hepatocytes have not been well characterized and quantitative target values for PHH alternatives remain unknown. In this study, we collected 179 data sheets of commercially available PHH lots from 4 vendors to clarify the characteristics of PHH in drug metabolism and DDI. We identified the most frequently observed value ranges (MFRs) of the activities of major drug metabolizing enzymes (CYP3A4/5, CYP1A2, CYP2C9, CYP2C19, CYP2D6, CYP2E1, UGT, and SULT) and drug transporters. Moreover, we also identified MFRs of fold changes of CYP inductions by each typical inducer both in the mRNA levels and the enzyme activity levels of CYP1A2, CYP2B6, and CYP3A. We suggest that these MFRs are the first milestone to develop and evaluate human iPS cell-derived hepatocytes as alternatives to PHH in pharmaceutical research for assessing absorption, distribution, metabolism, excretion, and toxicity.

fundamental toxicological sciences

Requirements for human iPS cell-derived hepatocytes as an alternative to primary human hepatocytes for assessing absorption, distribution, metabolism, excretion and toxicity of pharmaceuticals