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Novel Screening System for Biliary Excretion of Drugs Using Human Cholangiocyte Organoid Monolayers with Directional Drug Transport.
Mizoi, Kenta; Okada, Ryo; Mashimo, Arisa; Masuda, Norio; Itoh, Manabu; Ishida, Seiichi; Yamazaki, Daiju; Ogihara, Takuo.
Afiliación
  • Mizoi K; Faculty of Pharmacy, Takasaki University of Health and Welfare.
  • Okada R; School of Pharmacy, International University of Health and Welfare.
  • Mashimo A; JSR-Keio University Medical and Chemical Innovation Center (JKiC), JSR Corporation.
  • Masuda N; Faculty of Pharmacy, Takasaki University of Health and Welfare.
  • Itoh M; Kendai Translational Research Center (KTRC).
  • Ishida S; MEDICAL & BIOLOGICAL LABORATORIES CO., LTD. (MBL).
  • Yamazaki D; JSR-Keio University Medical and Chemical Innovation Center (JKiC), JSR Corporation.
  • Ogihara T; Division of Applied Life Science, Graduate School of Engineering, Sojo University.
Biol Pharm Bull ; 47(2): 427-433, 2024.
Article en En | MEDLINE | ID: mdl-38369341
ABSTRACT
It has recently been reported that cholangiocyte organoids can be established from primary human hepatocytes. The purpose of this study was to culture the organoids in monolayers on inserts to investigate the biliary excretory capacity of drugs. Cholangiocyte organoids prepared from hepatocytes had significantly higher mRNA expression of CK19, a bile duct epithelial marker, compared to hepatocytes. The organoids also expressed mRNA for efflux transporters involved in biliary excretion of drugs, P-glycoprotein (P-gp), multidrug resistance-associated protein 2 (MRP2), and breast cancer resistance protein (BCRP). The subcellular localization of each protein was observed. These results suggest that the membrane-cultured cholangiocyte organoids are oriented with the upper side being the apical membrane side (A side, bile duct lumen side) and the lower side being the basolateral membrane side (B side, hepatocyte side), and that each efflux transporter is localized to the apical membrane side. Transport studies showed that the permeation rate from the B side to the A side was faster than from the A side to the B side for the substrates of each efflux transporter, but this directionality disappeared in the presence of inhibitor of each transporter. In conclusion, the cholangiocyte organoid monolayer system has the potential to quantitatively evaluate the biliary excretion of drugs. The results of the present study represent an unprecedented system using human cholangiocyte organoids, which may be useful as a screening model to directly quantify the contribution of biliary excretion to the clearance of drugs.
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Proteínas Asociadas a Resistencia a Múltiples Medicamentos / Eliminación Hepatobiliar Límite: Humans Idioma: En Revista: Biol Pharm Bull Asunto de la revista: BIOQUIMICA / FARMACOLOGIA Año: 2024 Tipo del documento: Article Pais de publicación: Japón
Texto completo
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Proteínas Asociadas a Resistencia a Múltiples Medicamentos / Eliminación Hepatobiliar Límite: Humans Idioma: En Revista: Biol Pharm Bull Asunto de la revista: BIOQUIMICA / FARMACOLOGIA Año: 2024 Tipo del documento: Article Pais de publicación: Japón