- Tetsuro Araki (Consortium for Safety Assessment using Human iPS Cells (CSAHi) / Non-Clinical Evaluation Expert Committee, Drug Evaluation Committee, Japan Pharmaceutical Manufacturers Association / Laboratory for Safety Assessment and ADME, Pharmaceuticals Research Center, Asahi Kasei Pharma Corporation / email@example.com)
1) Consortium for Safety Assessment using Human iPS Cells (CSAHi) , 2) Non-Clinical Evaluation Expert Committee, Drug Evaluation Committee, Japan Pharmaceutical Manufacturers Association , 3) Laboratory for Safety Assessment and ADME, Pharmaceuticals Research Center, Asahi Kasei Pharma Corporation , 4) DMPK Research Laboratories, Mitsubishi Tanabe Pharma Corporation , 5) Pharmacokinetics and Non-Clinical Safety, Kobe Pharma Research Institute, Nippon Boehringer Ingelheim Co., Ltd. , 6) Drug Safety Research Laboratories, Astellas Pharma Inc. , 7) Analysis & Pharmacokinetics Research Laboratories, Astellas Pharma Inc. , 8) Drug Metabolism and Pharmacokinetics Japan, Tsukuba Research Laboratories, Eisai Co., Ltd. , 9) Kissei Pharmaceutical Co., Ltd. , 10) Mitsubishi Tanabe Pharma Corporation , 11) Shin Nippon Biomedical Laboratories, Ltd. , 12) Pharmacokinetics and Bioanalysis Center, Shin Nippon Biomedical Laboratories, Ltd. , 13) Safety Assessment Department, Research Division, Chugai Pharmaceutical Co., Ltd.
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.