Newsletter Volume 38, Number 1, 2023

Comments from the Award Winners


On receiving the Best Poster Award

Laboratory of Pharmacokinetics and Pharmacodynamics, Department of Drug Discovery Science, Kanazawa University Graduate School of Pharmaceutical Sciences
Laboratory of Pharmacokinetics

Yuya Nakazono

 Thank you very much for the Best Poster Award for the presentation entitled “A novel in vitro hepatocyte culture system for rapid evaluation of the biliary excretion of drugs” at the 37th Annual Meeting of the Japanese Pharmacokinetics Society. Thank you very much for the award. I would like to express my sincere gratitude to Dr. Hideki Hirabayashi, the President of the Annual Meeting, the selection committee members, and all the people involved in the Japanese Pharmacokinetics Society.

 Evaluation of drug biliary excretion via drug-metabolizing enzymes and transporters is very important because drug hepatobiliary kinetics is directly related to drug efficacy and safety. Currently, sandwich-cultured hepatocytes (SCH) are widely used as an in vitro model of drug biliary excretion. The drug secreted into the bile duct lumen must be recovered by breaking the adhesion bonds under Ca2+/Mg2+ free conditions and leaking the bile components, which is laborious and may cause cytotoxic effects by maintaining the Ca2+/Mg2+ free state. Therefore, the establishment of a rapid and quantitative in vitro evaluation system for drugs excreted in bile is an important issue.
Therefore, if a hepatocyte culture system with an open bile duct lumen on the culture medium side could be established, the drug excretion process in bile could be easily evaluated as transcellular transport by a permeation test, which would be a new evaluation system that overcomes the problem of SCH.

 In this study, we established induced open-form bile canaliculus hepatocyte (icHep), a hepatocyte with an open bile duct lumen on the vessel side, by culturing hepatocytes in a culture medium coated with claudin, a major factor in the adhesion bonding that is important for the formation of the bile duct lumen. We have established hepatocytes with an open bile duct lumen on the vessel side: induced open-form bile canaliculus hepatocyte (icHep). Permeabilization studies using typical substrates for bile excretion transporters in icHep showed unidirectional transport of each substrate from the blood side to the bile side. Furthermore, the estimated biliary clearance of drugs from icHep showed a good correlation with the reported in vivo clearance in humans. Therefore, we believe that the icHep permeation assay system can be used as a new biliary excretion evaluation system that enables easy and rapid recovery of drugs excreted in bile and estimation of the clearance of drugs excreted in bile.

 Finally, we would like to express our sincere gratitude to Professor Ikumi Tamai, Associate Professor Dai Arakawa, Associate Professor Yoshiyuki Shirasaka, students, and collaborators for their guidance in conducting this research.