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

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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.

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Change history

  • 21 February 2019

    There was a miscalculation of coproporphyrin I AUC0-24h in the published article (Volume 35, Number 7). After the correction of AUC0-24h, AUC ratio and R-square were re-calculated. Then, following corrections were made in the abstract, the body, Fig. 3, Fig. 4 and Table 2 in this article.



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










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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.

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Correspondence to Hiroyuki Kusuhara.

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Takehara, I., Yoshikado, T., Ishigame, K. et al. Comparative Study of the Dose-Dependence of OATP1B Inhibition by Rifampicin Using Probe Drugs and Endogenous Substrates in Healthy Volunteers. Pharm Res 35, 138 (2018).

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Key Words

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