YAMADA Yasuhiro, Ph.D. / Professor
Division of Clinical Pharmaceutics
Department of Pharmaceutical Sciences
1. The investigation of metabolism-mediated drug-drug interactions (DDIs).
2. The creation of human alternatives hepatocytes and enterocytes from stem cells or hepatoma cell lines.
3. The construction of an in vitro test system to evaluate chronic and idiosyncratic hepatotoxicity
In order to effectively overcome the "valley of death" in the process to drug development from discovery research and increase the probability of success, it is important to accurately predict pharmacokinetics and side effects (toxicity) for humans in new drug seeds (new chemical entities and/or drug candidates) at the pre-clinical stage. For that purpose, it becomes the key to stably supply high-quality human hepatocytes and enterocytes as research support tools.Hence, we are constructing a system to create human alternative hepatocytes and enterocytes using induced pluripotent stem (iPS) cells or cell fate transformation without the mediation of iPS cells (direct or epigenetic reprogramming), and constructing an evaluation system for predictions of clinical pharmacokinetics and DDIs using those cells. We are also studying three-dimensional co-cultures of human hepatocytes and heterologous cells to evaluate the chronic and idiosyncratic toxicity of drugs in vitro. In addition, in order to carry out the above-mentioned research more efficiently with robustness, development of a high-throughput drug concentration measurement method using a liquid chromatograph triple quadrupole mass spectrometer is also under consideration.
1. Katsuda T., Matsuzaki J., Yamaguchi T., Yamada Y., Prieto-Vila M., Hosaka K., Takeuchi A., Saito Y., Ochiya T., Generation of human hepatic progenitor cells with regenerative and metabolic capacities from primary hepatocytes. Elife, 8, pii: e47313 (2019).
2. Ogasawara A., Kato N., Torimoto N., Aohara F., Ohashi R., Yamada Y., Taniguchi H., Cytochrome P450 1A2 messenger RNA is a more reliable marker than cytochrome P450 1A2 activity, phenacetin O-deethylation, for assessment of induction potential of drug-metabolizing enzymes using HepaRG cells. Drug Metab Lett., 12(1),14-23 (2018).
3. Gailhouste L., Liew LC., Yasukawa K., Hagiwara K., Iwazaki N., Yamada Y., Hatada I., Ochiya T. Epigenetic reprogramming of human hepatoma cells: A low-cost option for drug metabolism assessment. Cell Mol Gastroenterol Hepatol., 5(3), 454-457 (2017).
4. Ogasawara A., Yamada Y., Torimoto N., Tsuda N., Aohara F., Ohashi R., Taniguchi H. New screening criteria setting on evaluation of cytochrome P450 induction using HepaRG cells with multiplex branched DNA technologies in early drug discovery. Drug Metab. Lett., 10(4), 152-160 (2016).
5. Kozakai K., Yamada Y., Oshikata M., Kawase T., Suzuki E., Haramaki Y., Taniguchi H. Cocktail-substrate approach-based high-throughput assay for evaluation of direct and time-dependent inhibition of multiple cytochrome P450 isoforms. Drug Metab Pharmacokinet., 29(2), 198-207 (2014).
6. Kozakai K., Yamada Y., Oshikata M., Kawase T., Suzuki E., Haramaki Y., Taniguchi H, Reliable high-throughput method for inhibition assay of 8 cytochrome P450 isoforms using cocktail of probe substrates and stable isotope-labeled internal standards. Drug Metab Pharmacokinet., 27(5), 520-529 (2012).
7. Kodera J., Michida H., Inoue H., Fijishige K., Sasaki T., Kobayashi T., Kojima K., Yss S., Yamada Y., Kikkawa K., Omori K., Avanafil, a potent and highly selective phosphodiesterase-5 inhibitor for erectile dysfunction. J Urol., 188(2), 668-674 (2012).
8. Yamada Y., Kaji H., Shion ., Oshikata M., Haramaki Y., Successful application for distribution image of chloroquine in ocular tissue of pigmented rat using MALDI-imaging quadrupole time-of-flight mass spectrometry. Rapid Commun Mass Spectrom., 25(11), 1600-1608 (2011).
9. Yamada Y. High-throughput analysis technique in the drug discovery stage. Nihon Yakurigaku Zasshi, 135(3), 109-112