Pharmaceutical Research

, Volume 34, Issue 8, pp 1570–1583 | Cite as

A Clinical Cassette Dosing Study for Evaluating the Contribution of Hepatic OATPs and CYP3A to Drug-Drug Interactions

  • Takashi Yoshikado
  • Kazuya Maeda
  • Sawako Furihata
  • Hanano Terashima
  • Takeshi Nakayama
  • Keiko Ishigame
  • Kazunobu Tsunemoto
  • Hiroyuki Kusuhara
  • Ken-ichi Furihata
  • Yuichi SugiyamaEmail author
Research Paper



To demonstrate the relative importance of organic anion-transporting polypeptides (OATPs) and cytochrome P450 3A (CYP3A) in the hepatic elimination of substrate drugs.


A cocktail of subtherapeutic doses of bosentan, repaglinide, clarithromycin, darunavir, simeprevir, and midazolam (CYP3A probe) was administered orally to eight healthy volunteers. Rifampicin (OATP inhibitor; 600 mg, p.o.) and itraconazole (CYP3A inhibitor; 200 mg, i.v.) were coadministered with the cocktail in the second and third phases, respectively. Based on the extended clearance concept, in vivo β values (fraction of metabolism plus biliary excretion among all the intracellular fates of drugs including basolateral efflux) and Rdif values (ratio of diffusional uptake to active uptake) were estimated.


Rifampicin increased plasma AUCs of bosentan (×3.2), repaglinide (×1.9), clarithromycin (×1.9) and simeprevir (×7.2). Itraconazole increased those of clarithromycin (×2.3), simeprevir (×2.2) and midazolam (×3.7), which had relatively small β values. The plasma AUC of bosentan (with relatively large β and small Rdif) was dominated by OATP-mediated uptake. The AUC of simeprevir was also dominated by OATP-mediated uptake because of its small Rdif value.


The DDI study clarified the rate-determining processes of OATP/CYP3A substrates. Our analyses provide valuable information for predicting complex drug–drug interactions involving multiple processes.

Key words

Extended clearance concept Hepatic uptake Metabolism Rate-determining process 



Area under the plasma concentration–time curve


AUC ratio




Hepatic clearance


Overall hepatic intrinsic clearance


Intrinsic clearance of biliary excretion


Intrinsic clearance of hepatic metabolism


Renal clearance


Cytochrome P450


Drug-drug interaction


University of Washington’s metabolism and transporter drug interaction database program


Extended clearance classification system


Extended clearance concept classification system


Fraction of the oral dose that enters the gut wall


Protein unbound fraction in blood


Fraction of drug passing on to the portal circulation


Hepatic availability


Contribution of CYP3A to the overall metabolic activity


Fraction of OATP1Bs-mediated transport in the hepatic intrinsic uptake clearance


Inhibition ratio for CYP3A by itraconazole


Inhibition ratio for OATP1Bs by rifampicin


in vitro-in vivo extrapolation


Na+-taurocholate cotransporting polypeptide


Organic anion transporting polypeptide


Physiologically-based pharmacokinetic


Permeability surface area-product


Intrinsic active efflux clearance on sinusoidal membrane


Intrinsic active uptake clearance on sinusoidal membrane


Intrinsic efflux clearance by passive diffusion on sinusoidal membrane


Intrinsic influx clearance by passive diffusion on sinusoidal membrane


Hepatic blood flow rate


Blood-to-plasma concentration ratio


Ratio of PSdif,inf to PSact,inf


Sandwich-cultured human hepatocyte




Acknowledgements and Disclosures

This study was financially supported by Grant-in-Aid for Scientific Research (S) [Grant 24,229,002; TY, KM, YS].

Author Contributions

Wrote Manuscript: Takashi Yoshikado, Kazuya Maeda, Hiroyuki Kusuhara, and Yuichi Sugiyama.

Designed Research: Takashi Yoshikado, Kazuya Maeda, Sawako Furihata, Hiroyuki Kusuhara, Ken-ichi Furihata and Yuichi Sugiyama.

Performed Research: Takashi Yoshikado, Kazuya Maeda, Sawako Furihata, Hanano Terashima, Takeshi Nakayama, Keiko Ishigame, Kazunobu Tsunemoto, Hiroyuki Kusuhara, Ken-ichi Furihata and Yuichi Sugiyama.

Analyzed Data: Takashi Yoshikado, Kazuya Maeda, Hiroyuki Kusuhara, and Yuichi Sugiyama.

Supplementary material

11095_2017_2168_MOESM1_ESM.pdf (1.1 mb)
ESM 1 (PDF 1.13 MB)


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Copyright information

© Springer Science+Business Media New York 2017

Authors and Affiliations

  • Takashi Yoshikado
    • 1
  • Kazuya Maeda
    • 2
  • Sawako Furihata
    • 3
  • Hanano Terashima
    • 2
  • Takeshi Nakayama
    • 2
  • Keiko Ishigame
    • 1
  • Kazunobu Tsunemoto
    • 1
  • Hiroyuki Kusuhara
    • 2
  • Ken-ichi Furihata
    • 3
  • Yuichi Sugiyama
    • 1
    Email author
  1. 1.Sugiyama LaboratoryRIKEN Innovation Center, RIKENYokohamaJapan
  2. 2.Laboratory of Molecular Pharmacokinetics, Graduate School of Pharmaceutical SciencesThe University of TokyoTokyoJapan
  3. 3.Keikokai Medical CorporationP-One ClinicTokyoJapan

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