Comments from the Award Winners

On receiving the Best Poster Award Laboratory of Molecular Pharmacotherapeutics, Department of Pharmaceutical Sciences, Kanazawa University Naoki Ishida

　I am very honored to receive the Best Poster Award at the 37th Annual Meeting of the Japanese Pharmacokinetics Society. Capecitabine is an oral prodrug of 5-fluorouracil, which is an important drug for the treatment of various solid tumors such as colorectal cancer and breast cancer. Capecitabine is an oral prodrug of 5-fluorouracil and plays an important role in the pharmacotherapy of various solid tumors such as colorectal and breast cancer. Genome-wide association analysis has shown that the risk of hand-foot syndrome is associated with mutations in the organic anion transporter 2 (OAT2/SLC22A7) gene (rs2270860, C>T), but the molecular mechanism of this association is unknown. Capecitabine is hydrolyzed and activated by carboxylesterase (CES), which has a catalytic site in the endoplasmic reticulum lumen of the liver. We hypothesized that OAT2 is involved in capecitabine permeation through the endoplasmic reticulum membrane and attempted to elucidate the role of OAT2 in capecitabine hydrolysis in the liver. We investigated the relationship between OAT2 mutations and capecitabine plasma concentration profiles in colorectal cancer patients. The results showed that the half-life of capecitabine in patients with rs2270860 was longer than that in wild-type patients. Next, immunostaining of human liver sections was performed to clarify the subcellular localization of OAT2, which was shown to be localized in the endoplasmic reticulum. Furthermore, the amount of hydrolysis products of capecitabine in primary cultured human hepatocytes decreased in the presence of ketoprofen, an OAT2 inhibitor. On the other hand, ketoprofen had no effect on the intracellular uptake of capecitabine, and the hydrolytic activity of capecitabine in human liver microsomes permeabilized with alamethicin through the endoplasmic reticulum membrane was not inhibited by ketoprofen The hydrolytic activity of capecitabine in human liver microsomes permeabilized with alamethicin was not inhibited by ketoprofen. These results suggest that OAT2 is involved in the ER uptake process of capecitabine and regulates capecitabine retention in human blood. In the future, we would like to investigate the effects of genetic mutation of OAT2 on protein expression and function, and its relationship with hand-foot syndrome. Finally, we would like to take this opportunity to express our sincere gratitude to Associate Professor Dai Arakawa, Professor Masao Kato, Professor Kenichi Fujita, Lecturer Natsumi Matsumoto, and Laboratory of Molecular Pharmacotherapy, Kanazawa University, and Showa University, for their guidance and support in conducting this study.