Pharmaceutical Research

, 35:138 | Cite as

Comparative Study of the Dose-Dependence of OATP1B Inhibition by Rifampicin Using Probe Drugs and Endogenous Substrates in Healthy Volunteers

  • Issey Takehara
  • Takashi Yoshikado
  • Keiko Ishigame
  • Daiki Mori
  • Ken-ichi Furihata
  • Nobuaki Watanabe
  • Osamu Ando
  • Kazuya Maeda
  • Yuichi Sugiyama
  • Hiroyuki KusuharaEmail author
Research Paper



To evaluate association of the dose-dependent effect of rifampicin, an OATP1B inhibitor, on the plasma concentration–time profiles among OATP1B substrates drugs and endogenous substrates.


Eight healthy volunteers received atorvastatin (1 mg), pitavastatin (0.2 mg), rosuvastatin (0.5 mg), and fluvastatin (2 mg) alone or with rifampicin (300 or 600 mg) in a crossover fashion. The plasma concentrations of these OATP1B probe drugs, total and direct bilirubin, glycochenodeoxycholate-3-sulfate (GCDCA-S), and coproporphyrin I, were determined.


The most striking effect of 600 mg rifampicin was on atorvastatin (6.0-times increase) and GCDCA-S (10-times increase). The AUC0–24h of atorvastatin was reasonably correlated with that of pitavastatin (r2 = 0.73) and with the AUC0–4h of fluvastatin (r2 = 0.62) and sufficiently with the AUC0–24h of rosuvastatin (r2 = 0.32). The AUC0–24h of GCDCA-S was reasonably correlated with those of direct bilirubin (r2 = 0.74) and coproporphyrin I (r2 = 0.80), and sufficiently with that of total bilirubin (r2 = 0.30). The AUC0–24h of GCDCA-S, direct bilirubin, and coproporphyrin I were reasonably correlated with that of atorvastatin (r2 = 0.54–0.70).


These results suggest that direct bilirubin, GCDCA-S, and coproporphyrin I are promising surrogate probes for the quantitative assessment of potential OATP1B-mediated DDI.

Key Words

drug–drug interaction endogenous substrates hepatobiliary transport organic anion transporter surrogate probe 



Area under the plasma concentration–time curve


Breast cancer resistance protein








Cytochrome P-450


Drug–drug interaction










High performance liquid chromatography


Liquid chromatography–tandem mass spectrometry


Multiple reaction monitoring


Sodium-taurocholate cotransporting polypeptide


Organic anion transporter


Organic anion-transporting polypeptide 1B1


Organic anion-transporting polypeptide 1B3


Organic anion-transporting polypeptide 2B1










Acknowledgments and Disclosures

The authors thank Miwa Yoshida (P-One Clinic) for her technical support in conducting the clinical research, and Drs. Ragu Ramanathan, Amanda King-Ahmad, and David Rodrigues (Pfizer, Groton, CT) for their kind support in introducing their analytical method for coproporphyrins I and III to this study. This study was financially supported by a Grant-in-Aid for Scientific Research (S) [Grant 24,229,002], and Grant-in-Aid for Scientific Research (B) [17H04100] from Japan Society for the Promotion of Science, and a Grant-in-Aid from the Japan Research Foundation for Clinical Pharmacology.

Supplementary material

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ESM 1 (DOCX 29.1 kb)
11095_2018_2416_MOESM2_ESM.docx (1 mb)
ESM 2 (DOCX 1068 kb)


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Copyright information

© Springer Science+Business Media, LLC, part of Springer Nature 2018

Authors and Affiliations

  • Issey Takehara
    • 1
    • 2
  • Takashi Yoshikado
    • 3
    • 4
  • Keiko Ishigame
    • 4
  • Daiki Mori
    • 2
  • Ken-ichi Furihata
    • 5
  • Nobuaki Watanabe
    • 6
  • Osamu Ando
    • 6
  • Kazuya Maeda
    • 2
  • Yuichi Sugiyama
    • 4
  • Hiroyuki Kusuhara
    • 2
    Email author
  1. 1.Biomarker DepartmentDaiichi Sankyo Co. Ltd.TokyoJapan
  2. 2.Laboratory of Molecular Pharmacokinetics, Graduate School of Pharmaceutical SciencesThe University of TokyoTokyoJapan
  3. 3.Laboratory of Clinical PharmacologyYokohama University of PharmacyYokohama-shiJapan
  4. 4.Sugiyama Laboratory, RIKEN Innovation CenterRIKENYokohamaJapan
  5. 5.P-One ClinicKeikokai Medical CorpTokyoJapan
  6. 6.Drug Metabolism & Pharmacokinetics Research LaboratoriesDaiichi Sankyo Co., Ltd.TokyoJapan

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