Pharmaceutical Research

, Volume 34, Issue 8, pp 1601–1614 | Cite as

Investigation of Glycochenodeoxycholate Sulfate and Chenodeoxycholate Glucuronide as Surrogate Endogenous Probes for Drug Interaction Studies of OATP1B1 and OATP1B3 in Healthy Japanese Volunteers

  • Issey Takehara
  • Hanano Terashima
  • Takeshi Nakayama
  • Takashi Yoshikado
  • Miwa Yoshida
  • Kenichi Furihata
  • Nobuaki Watanabe
  • Kazuya Maeda
  • Osamu Ando
  • Yuichi Sugiyama
  • Hiroyuki KusuharaEmail author
Research Paper



To assess the use of glycochenodeoxycholate-3-sulfate (GCDCA-S) and chenodeoxycholate 3- or 24-glucuronide (CDCA-3G or -24G) as surrogate endogenous substrates in the investigation of drug interactions involving OATP1B1 and OATP1B3.


Uptake of GCDCA-S and CDCA-24G was examined in HEK293 cells transfected with cDNA for OATP1B1, OATP1B3, and NTCP and in cryopreserved human hepatocytes. Plasma concentrations of bile acids and their metabolites (GCDCA-S, CDCA-3G, and CDCA-24G) were determined by LC–MS/MS in eight healthy volunteers with or without administration of rifampicin (600 mg, po).


GCDCA-S and CDCA-24G were substrates for OATP1B1, OATP1B3, and NTCP. The uptake of [3H]atorvastatin, GCDCA-S, and CDCA-24G by human hepatocytes was significantly inhibited by both rifampicin and pioglitazone, whereas that of taurocholate was inhibited only by pioglitazone. Rifampicin elevated plasma concentrations of GCDCA-S more than those of other bile acids. The area under the plasma concentration–time curve for GCDCA-S was 20.3 times higher in rifampicin-treated samples. CDCA-24G could be detected only in plasma from the rifampicin-treatment phase, and CDCA-3G was undetectable in both phases.


We identified GCDCA-S and CDCA-24G as substrates of NTCP, OATP1B1, and OATP1B3. GCDCA-S is a surrogate endogenous probe for the assessment of drug interactions involving hepatic OATP1B1 and OATP1B3.


bile acids drug–drug interaction endogenous substrates hepatobiliary transport organic anion transporting polypeptide (OATP) 



ATP-binding cassette


Area under the plasma concentration–time curve


Breast cancer resistance protein


Bile salt export pump












Drug–drug interaction


Dehydroepiandrosterone sulfate


Farnesoid X receptor










Hexadecanedionic acid


Human embryonic kidney 293


Liquid chromatography–tandem mass spectrometry


Lower limit of quantification


Lower limit of quantitation


Multiple reaction monitoring


Multidrug resistance-associated protein


Sodium-taurocholate cotransporting polypeptide


Organic anion transporter


Organic anion transporting polypeptide 1B1


Organic anion transporting polypeptide 1B3


Organic anion transporting polypeptide 2B1


Positron emission tomography


Small heterodimer partner.






Tetradecanedionic acid










Acknowledgments and Disclosures

This study was financially supported partly by a Grant-in-Aid for Scientific Research (S) [Grant 24,229,002], partly by the Research on Development of New Drugs from the Japan Agency for Medical Research and Development, and partly by a Grant-in-Aid from the Japan Research Foundation for Clinical Pharmacology.

Author Contributions

Wrote Manuscript: Issey Takehara, Nobuaki Watanabe, Kazuya Maeda, Osamu Ando, Yuichi Sugiyama, and Hiroyuki Kusuhara

Designed Research: Issey Takehara, Takashi Yoshikado, Miwa Yoshida, Kenichi Furihata, Nobuaki Watanabe, Kazuya Maeda, Osamu Ando, Yuichi Sugiyama, and Hiroyuki Kusuhara

Performed Research: Issey Takehara, Hanano Terashima, Takeshi Nakayama, Kazuya Maeda

Analyzed Data: Takehara, Hanano Terashima, Nobuaki Watanabe, Kazuya Maeda, Yuichi Sugiyama, and Hiroyuki Kusuhara

Supplementary material

11095_2017_2184_MOESM1_ESM.docx (1.3 mb)
ESM 1 (DOCX 1288 kb)


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Copyright information

© Springer Science+Business Media New York 2017

Authors and Affiliations

  • Issey Takehara
    • 1
    • 2
    • 3
  • Hanano Terashima
    • 2
  • Takeshi Nakayama
    • 2
  • Takashi Yoshikado
    • 4
  • Miwa Yoshida
    • 5
  • Kenichi Furihata
    • 5
  • Nobuaki Watanabe
    • 1
  • Kazuya Maeda
    • 2
  • Osamu Ando
    • 1
  • Yuichi Sugiyama
    • 4
  • Hiroyuki Kusuhara
    • 2
    Email author
  1. 1.Drug Metabolism & Pharmacokinetics Research LaboratoriesDaiichi Sankyo Co., Ltd.TokyoJapan
  2. 2.Laboratory of Molecular Pharmacokinetics, Graduate School of Pharmaceutical SciencesThe University of TokyoTokyoJapan
  3. 3.Biomarker DepartmentDaiichi Sankyo Co., Ltd.TokyoJapan
  4. 4.Sugiyama LaboratoryRIKEN Innovation Center, RIKENYokohamaJapan
  5. 5.P-One Clinic, Keikokai Medical CorpTokyoJapan

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