ACS Publications. Most Trusted. Most Cited. Most Read
My Activity

Uptake of Ursodeoxycholate and Its Conjugates by Human Hepatocytes:  Role of Na+-Taurocholate Cotransporting Polypeptide (NTCP), Organic Anion Transporting Polypeptide (OATP) 1B1 (OATP-C), and OATP1B3 (OATP8)

View Author Information
Graduate School of Pharmaceutical Sciences, University of Tokyo, Tokyo, Japan, and Department of Medicine, University of California, San Diego, California
Cite this: Mol. Pharm. 2006, 3, 1, 70–77
Publication Date (Web):December 15, 2005
Copyright © 2006 American Chemical Society

    Article Views





    Other access options


    Abstract Image

    Ursodeoxycholate (UDCA) is widely used for the treatment of cholestatic liver disease. After oral administration, UDCA is absorbed, taken up efficiently by hepatocytes, and conjugated mainly with glycine to form glycoursodeoxycholate (GUDC) or partly with taurine to form tauroursodeoxycholate (TUDC), which undergo enterohepatic circulation. In this study, to check whether three basolateral transportersNa+-taurocholate cotransporting polypeptide (NTCP, SLC10A1), organic anion transporting polypeptide (OATP) 1B1 (OATP-C), and OATP1B3 (OATP8)mediate uptake of UDCA, GUDC, and TUDC by human hepatocytes, we investigated their transport properties using transporter-expressing HEK293 cells and human cryopreserved hepatocytes. TUDC and GUDC could be taken up via human NTCP, OATP1B1, and OATP1B3, whereas UDCA could be transported significantly by NTCP, but not OATP1B1 and OATP1B3 in our expression systems. We observed a time-dependent and saturable uptake of UDCA and its conjugates by human cryopreserved hepatocytes, and more than half of the overall uptake involved a saturable component. Kinetic analyses revealed that the contribution of Na+-dependent and -independent pathways to the uptake of UDCA or TUDC was very similar, while the Na+-independent uptake of GUDC was predominant. These results suggest that UDCA and its conjugates are taken up by both multiple saturable transport systems and nonsaturable transport in human liver with different contributions. These results provide an explanation for the efficient hepatic clearance of UDCA and its conjugates in patients receiving UDCA therapy.

    Keywords: Ursodeoxycholate; organic anion transporting polypeptide; OATP; Na+-taurocholate cotransporting polypeptide (NTCP); hepatic uptake; human hepatocytes

    Read this article

    To access this article, please review the available access options below.

    Get instant access

    Purchase Access

    Read this article for 48 hours. Check out below using your ACS ID or as a guest.


    Access through Your Institution

    You may have access to this article through your institution.

    Your institution does not have access to this content. You can change your affiliated institution below.

     University of Tokyo.

     University of California.


     Corresponding author. Mailing address:  Department of Molecular Pharmacokinetics, Graduate School of Pharmaceutical Sciences, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-0033, Japan. Tel:  +81-3-5841-4770. Fax:  +81-3-5841-4766. E-mail:  [email protected].

    Cited By

    This article is cited by 62 publications.

    1. Christine C. Orozco, Mikko Neuvonen, Yi-An Bi, Matthew A. Cerny, Sumathy Mathialagan, Laurie Tylaska, Brian Rago, Chester Costales, Amanda King-Ahmad, Mikko Niemi, A. David Rodrigues. Characterization of Bile Acid Sulfate Conjugates as Substrates of Human Organic Anion Transporting Polypeptides. Molecular Pharmaceutics 2023, 20 (6) , 3020-3032.
    2. Henriette E. Meyer zu Schwabedissen and Richard B. Kim . Hepatic OATP1B Transporters and Nuclear Receptors PXR and CAR: Interplay, Regulation of Drug Disposition Genes, and Single Nucleotide Polymorphisms. Molecular Pharmaceutics 2009, 6 (6) , 1644-1661.
    3. Grace Hoyee Chan, Robert Houle, Jinghui Zhang, Ravi Katwaru, Yang Li, Xiaoyan Chu. Evaluation of the Selectivity of Several Organic Anion Transporting Polypeptide 1B Biomarkers Using Relative Activity Factor Method. Drug Metabolism and Disposition 2023, 51 (9) , 1089-1104.
    4. Gergely Gyimesi, Matthias A. Hediger. Transporter-Mediated Drug Delivery. Molecules 2023, 28 (3) , 1151.
    5. Magdalena A. Maj, Tanvi R. Gehani, Chad Immoos, Mikaelah S. Medrano, Rob K. Fanter, Christine R. Strand, Hunter Glanz, Brian D. Piccolo, Mohammed K. Abo-Ismail, Michael R. La Frano, Rodrigo Manjarín. Olive- and Coconut-Oil-Enriched Diets Decreased Secondary Bile Acids and Regulated Metabolic and Transcriptomic Markers of Brain Injury in the Frontal Cortexes of NAFLD Pigs. Brain Sciences 2022, 12 (9) , 1193.
    6. Tao Hu, Hongbing Wang. Hepatic Bile Acid Transporters in Drug‐Induced Cholestasis. 2021, 307-337.
    7. Hyo-jeong Ryu, Hyun-ki Moon, Junho Lee, Gi-hyeok Yang, Sung-yoon Yang, Hwi-yeol Yun, Jung-woo Chae, Won-ho Kang. Evaluation for Potential Drug–Drug Interaction of MT921 Using In Vitro Studies and Physiologically–Based Pharmacokinetic Models. Pharmaceuticals 2021, 14 (7) , 654.
    8. Jingli Cai, Zhaowen Wang, Guiming Chen, Dapeng Li, Jun Liu, Hai Hu, Jian Qin. Reabsorption of bile acids regulated by FXR-OATP1A2 is the main factor for the formation of cholesterol gallstone. American Journal of Physiology-Gastrointestinal and Liver Physiology 2020, 319 (3) , G303-G308.
    9. James J. Beaudoin, Kim L.R. Brouwer, Melina M. Malinen. Novel insights into the organic solute transporter alpha/beta, OSTα/β: From the bench to the bedside. Pharmacology & Therapeutics 2020, 211 , 107542.
    10. Yingmin Nie, Jingjie Yang, Shuai Liu, Ruiqi Sun, Huihui Chen, Nan Long, Rui Jiang, Chunshan Gui. Genetic polymorphisms of human hepatic OATPs: functional consequences and effect on drug pharmacokinetics. Xenobiotica 2020, 50 (3) , 297-317.
    11. Yoshitane Nozaki, Saki Izumi. Recent advances in preclinical in vitro approaches towards quantitative prediction of hepatic clearance and drug-drug interactions involving organic anion transporting polypeptide (OATP) 1B transporters. Drug Metabolism and Pharmacokinetics 2020, 35 (1) , 56-70.
    12. Martha Paluschinski, Mirco Castoldi, David Schöler, Nils Bardeck, Jessica Oenarto, Boris Görg, Dieter Häussinger. Tauroursodeoxycholate protects from glycochenodeoxycholate-induced gene expression changes in perfused rat liver. Biological Chemistry 2019, 400 (12) , 1551-1565.
    13. Ruipu Sun, Ying Ying, Zhimin Tang, Ting Liu, Fuli Shi, Huixia Li, Taichen Guo, Shibo Huang, Ren Lai. The Emerging Role of the SLCO1B3 Protein in Cancer Resistance. Protein & Peptide Letters 2019, 27 (1) , 17-29.
    14. Dandan Zhou, Linghua Kong, Yiguo Jiang, Cheng Wang, Yao Ni, Yedong Wang, Hongjian Zhang, Jianqing Ruan. UGT-dependent regioselective glucuronidation of ursodeoxycholic acid and obeticholic acid and selective transport of the consequent acyl glucuronides by OATP1B1 and 1B3. Chemico-Biological Interactions 2019, 310 , 108745.
    15. Xiaoyang Lu, Lin Liu, Wenya Shan, Limin Kong, Na Chen, Yan Lou, Su Zeng. The Role of the Sodium-taurocholate Co-transporting Polypeptide (NTCP) and Bile Salt Export Pump (BSEP) in Related Liver Disease. Current Drug Metabolism 2019, 20 (5) , 377-389.
    16. Xiangyu Wu, Chen Gong, Justin Weinstock, Jun Cheng, Shengnan Hu, Scott A. Venners, Yi-Hsiang Hsu, Suwen Wu, Xiangdong Zha, Shanqun Jiang, Yong Li, Faming Pan, Xiping Xu. Associations of the SLCO1B1 Polymorphisms With Hepatic Function, Baseline Lipid Levels, and Lipid-lowering Response to Simvastatin in Patients With Hyperlipidemia. Clinical and Applied Thrombosis/Hemostasis 2018, 24 (9_suppl) , 240S-247S.
    17. Beáta Tóth, Márton Jani, Erzsébet Beéry, Teresa Heslop, Mark Bayliss, Neil R. Kitteringham, B. Kevin Park, Richard J. Weaver, Peter Krajcsi. Human OATP1B1 (SLCO1B1) transports sulfated bile acids and bile salts with particular efficiency. Toxicology in Vitro 2018, 52 , 189-194.
    18. George Mells, Graeme Alexander. Liver Function in Health and Disease. 2018, 20-38.
    19. Fabian Müller, Ashish Sharma, Jörg König, Martin F. Fromm, . Biomarkers for In Vivo Assessment of Transporter Function. Pharmacological Reviews 2018, 70 (2) , 246-277.
    20. Romil Saxena. Intrahepatic Cholestasis. 2018, 445-464.
    21. Ya Chen, Wen Zheng Zhang, Jing Li, Tao Xiao, Jiang Xia Liu, Min Luo, Hang Su, Xiao-Zhong Fu, Ting Liu, Yong-Xi Dong, Yong-Long Zhao, Bin He, Yong-Jun Li. Novel adefovir mono L-amino acid ester, mono bile acid ester derivatives: Design, synthesis, biological evaluation, and molecular docking study. Medicinal Chemistry Research 2017, 26 (8) , 1812-1821.
    22. Hong Shen, Weiqi Chen, Dieter M. Drexler, Sandhya Mandlekar, Vinay K. Holenarsipur, Eric E. Shields, Robert Langish, Kurex Sidik, Jinping Gan, W. Griffith Humphreys, Punit Marathe, Yurong Lai. Comparative Evaluation of Plasma Bile Acids, Dehydroepiandrosterone Sulfate, Hexadecanedioate, and Tetradecanedioate with Coproporphyrins I and III as Markers of OATP Inhibition in Healthy Subjects. Drug Metabolism and Disposition 2017, 45 (8) , 908-919.
    23. Rhishikesh Thakare, Hongying Gao, Rachel E. Kosa, Yi-An Bi, Manthena V. S. Varma, Matthew A. Cerny, Raman Sharma, Max Kuhn, Bingshou Huang, Yiping Liu, Aijia Yu, Gregory S. Walker, Mark Niosi, Larry Tremaine, Yazen Alnouti, A. David Rodrigues. Leveraging of Rifampicin-Dosed Cynomolgus Monkeys to Identify Bile Acid 3-O-Sulfate Conjugates as Potential Novel Biomarkers for Organic Anion-Transporting Polypeptides. Drug Metabolism and Disposition 2017, 45 (7) , 721-733.
    24. Takahiro Suga, Hiroaki Yamaguchi, Toshihiro Sato, Masamitsu Maekawa, Junichi Goto, Nariyasu Mano, . Preference of Conjugated Bile Acids over Unconjugated Bile Acids as Substrates for OATP1B1 and OATP1B3. PLOS ONE 2017, 12 (1) , e0169719.
    25. Alexander D. Roth, Moo-Yeal Lee. Idiosyncratic Drug-Induced Liver Injury (IDILI): Potential Mechanisms and Predictive Assays. BioMed Research International 2017, 2017 , 1-23.
    26. Miao Hu, Benny SP Fok, Siu‐Kwan Wo, Vincent HL Lee, Zhong Zuo, Brian Tomlinson. Effect of common polymorphisms of the farnesoid X receptor and bile acid transporters on the pharmacokinetics of ursodeoxycholic acid. Clinical and Experimental Pharmacology and Physiology 2016, 43 (1) , 34-40.
    27. Albert P. Li. Evaluation of Adverse Drug Properties with Cryopreserved Human Hepatocytes and the Integrated Discrete Multiple Organ Co-culture (IdMOC TM ) System. Toxicological Research 2015, 31 (2) , 137-149.
    28. Jin Gu Cho, Jun Hee Lee, Shin Hee Hong, Han Na Lee, Chul Min Kim, Seo Yoon Kim, Kang Jun Yoon, Bae Jun Oh, Jae Hyeon Kim, Seok Yoon Jung, Takayuki Asahara, Sang-Mo Kwon, Sang Gyu Park. Tauroursodeoxycholic Acid, a Bile Acid, Promotes Blood Vessel Repair by Recruiting Vasculogenic Progenitor Cells. Stem Cells 2015, 33 (3) , 792-805.
    29. Ziru Yan, Eqiong Li, Lingfei He, Jianhua Wang, Xiaojun Zhu, Hanzhi Wang, Zhengping Wang. Role of OATP1B3 in the transport of bile acids assessed using first‐trimester trophoblasts. Journal of Obstetrics and Gynaecology Research 2015, 41 (3) , 392-401.
    30. Zhongqi Dong, Sean Ekins, James E. Polli. A substrate pharmacophore for the human sodium taurocholate co-transporting polypeptide. International Journal of Pharmaceutics 2015, 478 (1) , 88-95.
    31. Michele Bonus, Annika Sommerfeld, Dieter Häussinger, Holger Gohlke. α5β1 integrins in hepatocytes act as receptors for bile acids with a (nor)ursodeoxycholane scaffold. European Journal of Medical Research 2014, 19 (S1)
    32. A Yamada, K Maeda, K Kiyotani, T Mushiroda, Y Nakamura, Y Sugiyama. Kinetic Interpretation of the Importance of OATP1B3 and MRP2 in Docetaxel-Induced Hematopoietic Toxicity. CPT: Pharmacometrics & Systems Pharmacology 2014, 3 (7) , 126.
    33. Tatehiro Kagawa, Reiko Orii, Shunji Hirose, Yoshitaka Arase, Koichi Shiraishi, Akiko Mizutani, Hidekazu Tsukamoto, Tetsuya Mine. Ursodeoxycholic acid stabilizes the bile salt export pump in the apical membrane in MDCK II cells. Journal of Gastroenterology 2014, 49 (5) , 890-899.
    34. Zhi-Yu ZHANG, Duan-Yun SI, Xiu-Lin YI, Chang-Xiao LIU. Inhibitory effect of medicinal plant-derived carboxylic acids on the human transporters hOAT1, hOAT3, hOATP1B1, and hOATP2B1. Chinese Journal of Natural Medicines 2014, 12 (2) , 131-138.
    35. Albert P Li. Biomarkers and human hepatocytes. Biomarkers in Medicine 2014, 8 (2) , 173-183.
    36. Walee Chamulitrat, Gerhard Liebisch, Weihong Xu, Hongying Gan-Schreier, Anita Pathil, Gerd Schmitz, Wolfgang Stremmel. Ursodeoxycholyl Lysophosphatidylethanolamide Inhibits Lipoapoptosis by Shifting Fatty Acid Pools toward Monosaturated and Polyunsaturated Fatty Acids in Mouse Hepatocytes. Molecular Pharmacology 2013, 84 (5) , 696-709.
    37. Eva Ramboer, Tamara Vanhaecke, Vera Rogiers, Mathieu Vinken. Primary hepatocyte cultures as prominent in vitro tools to study hepatic drug transporters. Drug Metabolism Reviews 2013, 45 (2) , 196-217.
    38. Bruno Hagenbuch, Bruno Stieger. The SLCO (former SLC21) superfamily of transporters. Molecular Aspects of Medicine 2013, 34 (2-3) , 396-412.
    39. Jörg König, Martin F. Fromm. OATP1B1, OATP1B3, and OATP2B1. 2013, 141-169.
    40. Yurong Lai. Organic anion-transporting polypeptides (OATPs/SLCOs). 2013, 353-454.
    41. Yuki Ikebuchi, Hidetoshi Shimizu, Kousei Ito, Takashi Yoshikado, Yoshihide Yamanashi, Tappei Takada, Hiroshi Suzuki. Ursodeoxycholic acid stimulates the formation of the bile canalicular network. Biochemical Pharmacology 2012, 84 (7) , 925-935.
    42. Jörg König, Sabine Klatt, Karin Dilger, Martin F. Fromm. Characterization of Ursodeoxycholic and Norursodeoxycholic Acid as Substrates of the Hepatic Uptake Transporters OATP 1B1, OATP 1B3, OATP 2B1 and NTCP. Basic & Clinical Pharmacology & Toxicology 2012, 111 (2) , 81-86.
    43. Tadayuki Takashima, Satoshi Kitamura, Yasuhiro Wada, Masaaki Tanaka, Yoshihito Shigihara, Hideki Ishii, Ryosuke Ijuin, Susumu Shiomi, Takahiro Nakae, Yumiko Watanabe, Yilong Cui, Hisashi Doi, Masaaki Suzuki, Kazuya Maeda, Hiroyuki Kusuhara, Yuichi Sugiyama, Yasuyoshi Watanabe. PET Imaging–Based Evaluation of Hepatobiliary Transport in Humans with (15 R )- 11 C-TIC-Me. Journal of Nuclear Medicine 2012, 53 (5) , 741-748.
    44. Megan Roth, Amanda Obaidat, Bruno Hagenbuch. OATPs, OATs and OCTs: the organic anion and cation transporters of the SLCO and SLC22A gene superfamilies. British Journal of Pharmacology 2012, 165 (5) , 1260-1287.
    45. Xiaoqiang Xiang, Juha Vakkilainen, Janne T. Backman, Pertti J. Neuvonen, Mikko Niemi. No significant effect of the SLCO1B1 polymorphism on the pharmacokinetics of ursodeoxycholic acid. European Journal of Clinical Pharmacology 2011, 67 (11) , 1159-1167.
    46. Seo Yoon Kim, Yoo-Wook Kwon, Il Lae Jung, Jong-Hyuk Sung, Sang Gyu Park. Tauroursodeoxycholate (TUDCA) inhibits neointimal hyperplasia by suppression of ERK via PKCα-mediated MKP-1 induction. Cardiovascular Research 2011, 92 (2) , 307-316.
    47. Mikko Niemi, Marja K. Pasanen, Pertti J. Neuvonen, . Organic Anion Transporting Polypeptide 1B1: a Genetically Polymorphic Transporter of Major Importance for Hepatic Drug Uptake. Pharmacological Reviews 2011, 63 (1) , 157-181.
    48. Marwan Ghabril, Won Kyoo Cho. Bile Physiology and Transporter Proteins. 2011, 37-44.
    49. Jörg König. Uptake Transporters of the Human OATP Family. 2011, 1-28.
    50. Bruno Stieger. The Role of the Sodium-Taurocholate Cotransporting Polypeptide (NTCP) and of the Bile Salt Export Pump (BSEP) in Physiology and Pathophysiology of Bile Formation. 2011, 205-259.
    51. Christina Fahrmayr, Martin F. Fromm, Jörg König. Hepatic OATP and OCT uptake transporters: their role for drug-drug interactions and pharmacogenetic aspects. Drug Metabolism Reviews 2010, 42 (3) , 380-401.
    52. Yeon Yi Lee, Shin Hee Hong, Ye Jin Lee, Sung Soo Chung, Hye Seung Jung, Sang Gyu Park, Kyong Soo Park. Tauroursodeoxycholate (TUDCA), chemical chaperone, enhances function of islets by reducing ER stress. Biochemical and Biophysical Research Communications 2010, 397 (4) , 735-739.
    53. Albert P. Li, Chuang Lu. Evaluation of Inhibitors of Drug Metabolism in Human Hepatocytes. 2009, 423-441.
    54. Xiaoqiang Xiang, Yi Han, Mikko Neuvonen, Marja K. Pasanen, Annikka Kalliokoski, Janne T. Backman, Jouko Laitila, Pertti J. Neuvonen, Mikko Niemi. Effect of SLCO1B1 polymorphism on the plasma concentrations of bile acids and bile acid synthesis marker in humans. Pharmacogenetics and Genomics 2009, 19 (6) , 447-457.
    55. Kazuya Maeda, Hiroshi Suzuki, Yuichi Sugiyama. Hepatic Transport. 2008, 277-332.
    56. B. Hagenbuch, C. Gui. Xenobiotic transporters of the human organic anion transporting polypeptides (OATP) family. Xenobiotica 2008, 38 (7-8) , 778-801.
    57. Yi-Jing He, Wei Zhang, Jiang-Hua Tu, Julia Kirchheiner, Yao Chen, Dong Guo, Qing Li, Zhong-Yu Li, Hao Chen, Dong-Li Hu, Dan Wang, Hong-Hao Zhou. Hepatic Nuclear Factor 1α Inhibitor Ursodeoxycholic Acid Influences Pharmacokinetics of the Organic Anion Transporting Polypeptide 1B1 Substrate Rosuvastatin and Bilirubin. Drug Metabolism and Disposition 2008, 36 (8) , 1453-1456.
    58. Shingo Sakamoto, Hiroyuki Kusuhara, Kazutoshi Horie, Kohji Takahashi, Takahiko Baba, Jun Ishizaki, Yuichi Sugiyama. Identification of the Transporters Involved in the Hepatobiliary Transport and Intestinal Efflux of Methyl 1-(3,4-Dimethoxyphenyl)-3-(3-ethylvaleryl)-4-hydroxy-6,7,8-trimethoxy-2-naphthoate (S-8921) Glucuronide, a Pharmacologically Active Metabolite of S-8921. Drug Metabolism and Disposition 2008, 36 (8) , 1553-1561.
    59. Anne T Nies, Matthias Schwab, Dietrich Keppler. Interplay of conjugating enzymes with OATP uptake transporters and ABCC/MRP efflux pumps in the elimination of drugs. Expert Opinion on Drug Metabolism & Toxicology 2008, 4 (5) , 545-568.
    60. Stanley D.W. Miller, Catherine M. Greene, Caitriona McLean, Matthew W. Lawless, Clifford C. Taggart, Shane J. O'Neill, Noel G. McElvaney. Tauroursodeoxycholic acid inhibits apoptosis induced by Z alpha-1 antitrypsin via inhibition of bad. Hepatology 2007, 46 (2) , 496-503.
    61. Bruno Hagenbuch. Cellular entry of thyroid hormones by organic anion transporting polypeptides. Best Practice & Research Clinical Endocrinology & Metabolism 2007, 21 (2) , 209-221.
    62. Albert P. Li. Human hepatocytes: Isolation, cryopreservation and applications in drug development. Chemico-Biological Interactions 2007, 168 (1) , 16-29.

    Pair your accounts.

    Export articles to Mendeley

    Get article recommendations from ACS based on references in your Mendeley library.

    Pair your accounts.

    Export articles to Mendeley

    Get article recommendations from ACS based on references in your Mendeley library.

    You’ve supercharged your research process with ACS and Mendeley!

    STEP 1:
    Click to create an ACS ID

    Please note: If you switch to a different device, you may be asked to login again with only your ACS ID.

    Please note: If you switch to a different device, you may be asked to login again with only your ACS ID.

    Please note: If you switch to a different device, you may be asked to login again with only your ACS ID.

    Your Mendeley pairing has expired. Please reconnect