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Drug Metabolism and Personalized Therapy

Official journal of the European Society of Pharmacogenomics and Personalised Therapy

Editor-in-Chief: Llerena, Adrián

Ed. by Benjeddou, Mongi

Editorial Board: Chen, Bing / Dahl, Marja-Liisa / Devinsky, Ferdinand / Hirata, Rosario / Hubacek, Jaroslav A. / Ingelman-Sundberg, Magnus / Maitland-van der Zee, Anke-Hilse / Manolopoulos, Vangelis G. / Marc, Janja / Melichar, Bohuslav / Meyer, Urs A. / Nair, Sujit / Nofziger, Charity / Peiro, Ana / Sadee, Wolfgang / Salazar, Luis A. / Simmaco, Maurizio / Turpeinen, Miia / Schaik, Ron / Shin, Jae-Gook / Visvikis-Siest, Sophie / Zanger, Ulrich M.

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Volume 29, Issue 4


Inhibition of OATP-1B1 and OATP-1B3 by tyrosine kinase inhibitors

Varun Khurana
  • Division of Pharmaceutical Sciences, School of Pharmacy, University of Missouri-Kansas City, 2464 Charlotte Street, Kansas City, MO 64108-2718, USA
  • INSYS Therapeutics Inc, 444 South Ellis Road, Chandler, AZ 85224, USA
  • Other articles by this author:
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/ Mukul Minocha
  • Division of Pharmaceutical Sciences, School of Pharmacy, University of Missouri-Kansas City, 2464 Charlotte Street, Kansas City, MO 64108-2718, USA
  • Center for Translational Medicine, School of Pharmacy, University of Maryland Baltimore, 20 North Pine Street, Baltimore, MD 21201, USA
  • Other articles by this author:
  • De Gruyter OnlineGoogle Scholar
/ Dhananjay Pal
  • Division of Pharmaceutical Sciences, School of Pharmacy, University of Missouri-Kansas City, 2464 Charlotte Street, Kansas City, MO 64108-2718, USA
  • Other articles by this author:
  • De Gruyter OnlineGoogle Scholar
/ Ashim K. Mitra
  • Corresponding author
  • Division of Pharmaceutical Sciences, School of Pharmacy, University of Missouri-Kansas City, 2464 Charlotte Street, Kansas City, MO 64108-2718, USA
  • Email
  • Other articles by this author:
  • De Gruyter OnlineGoogle Scholar
Published Online: 2014-05-07 | DOI: https://doi.org/10.1515/dmdi-2014-0014


Background: The potential of tyrosine kinase inhibitors (TKIs) interacting with other therapeutics through hepatic uptake transporter inhibition has not been fully delineated in drug-drug interactions (DDIs). This study was designed to estimate the half-maximal inhibitory concentration (IC50) values of five small-molecule TKIs (pazopanib, nilotinib, vandetanib, canertinib and erlotinib) interacting with organic anion-transporting polypeptides (OATPs): OATP-1B1 and -1B3.

Methods: The IC50 values of TKIs and rifampicin (positive control) were determined by concentration-dependent inhibition of TKIs on cellular accumulation of radiolabeled probe substrates [3H]estrone sulfate and [3H]cholecystokinin octapeptide. Chinese hamster ovary cells transfected with humanized OATP-1B1 and OATP-1B3 transporter proteins, respectively, were utilized to carry out these studies.

Results: Pazopanib and nilotinib show inhibitory activity on OATP-1B1 transporter protein. IC50 values for rifampicin, pazopanib and nilotinib were 10.46±1.15, 3.89±1.21 and 2.78±1.13 μM, respectively, for OATP-1B1 transporter. Vandetanib, canertinib and erlotinib did not exhibit any inhibitory potency toward OATP-1B1 transporter protein. Only vandetanib expressed inhibitory potential toward OATP-1B3 transporter protein out of the five selected TKIs. IC50 values for rifampicin and vandetanib for OATP-1B3 transporter inhibition were 3.67±1.20 and 18.13±1.21 μM, respectively. No significant inhibition in the presence of increasing concentrations of pazopanib, nilotinib, canertinib and erlotinib were observed for OATP-1B3 transporter.

Conclusions: Because selected TKIs are inhibitors of OATP-1B1 and -1B3 expressed in hepatic tissue, these compounds can be regarded as molecular targets for transporter-mediated DDIs. These findings provide the basis for further preclinical and clinical studies investigating the transporter-based DDI potential of TKIs.

Keywords: drug-drug interactions; hepatic transporters; IC50 values; nilotinib; pazopanib; vandetanib


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About the article

Corresponding author: Ashim K. Mitra, PhD, Curators’ Professor and Chairman, Division of Pharmaceutical Sciences, School of Pharmacy, University of Missouri-Kansas City, 2464 Charlotte Street, Kansas City, MO 64108, USA, Phone: +1-816-235-1615, Fax: +1-816-235-5190, E-mail:

Received: 2014-03-09

Accepted: 2014-04-01

Published Online: 2014-05-07

Published in Print: 2014-12-01

Citation Information: Drug Metabolism and Drug Interactions, Volume 29, Issue 4, Pages 249–259, ISSN (Online) 2191-0162, ISSN (Print) 0792-5077, DOI: https://doi.org/10.1515/dmdi-2014-0014.

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