Accessible Unlicensed Requires Authentication Published by De Gruyter March 18, 2014

Role of OATP-1B1 and/or OATP-1B3 in hepatic disposition of tyrosine kinase inhibitors

Varun Khurana, Mukul Minocha, Dhananjay Pal and Ashim K. Mitra


Background: The metabolism of tyrosine kinase inhibitors (TKIs) is mainly mediated via hepatic route, but the mechanism responsible for their hepatocellular accumulation is still unknown. This study was designed to understand the contribution of organic anion transporting polypeptides (OATPs) in the hepatic uptake of selected TKIs – pazopanib, canertinib, erlotinib, vandetanib and nilotinib.

Methods: Michaelis-Menten (MM) kinetic parameters for TKIs were determined by concentration-dependent cellular accumulation of selected TKIs using Chinese hamster ovary cells – wild type as well as transfected with humanized OATP-1B1 and OATP-1B3 transporter proteins.

Results: The MM constant (Km) values of OATP-1B1 for nilotinib and vandetanib are 10.14±1.91 and 2.72±0.25 μM, respectively, and Vmax values of OATP-1B1 for nilotinib and vandetanib were 6.95±0.47 and 75.95±1.99 nmol/mg protein per minute, respectively. Likewise, Km values of OATP-1B3 for canertinib, nilotinib and vandetanib were 12.18±3.32, 7.84±1.43 and 4.37±0.79 μM, respectively, and Vmax values of OATP-1B3 for canertinib, nilotinib and vandetanib were 15.34±1.59, 6.75±0.42 and 194.64±10.58 nmol/mg protein per minute, respectively. Canertinib did not exhibit any substrate specificity toward OATP-1B1. Also, erlotinib and pazopanib did not exhibit any substrate specificity toward OATP-1B1 and -1B3.

Conclusions: Because selected TKIs are the substrates of OATP-1B1 and -1B3 expressed in hepatic tissue, these compounds can be regarded as molecular targets for transporter-mediated drug-drug interactions (DDIs). Any alteration in the function of these hepatic OATPs might account for the pharmacokinetic variability of TKIs.

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:


This work was supported by National Institutes of Health grant 1R01 AI071199. The authors highly appreciate Dr. Bruno Stieger for the generous gift of CHO-WT and OATP-1B type transporter protein transfected cell lines.

Conflict of interest statement

Authors’ conflict of interest disclosure: The authors stated that there are no conflicts of interest regarding the publication of this article. Research support played no role in the study design; in the collection, analysis, and interpretation of data; in the writing of the report; or in the decision to submit the report for publication.

Research funding: None declared.

Employment or leadership: None declared.

Honorarium: None declared.


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Received: 2013-11-21
Accepted: 2014-2-12
Published Online: 2014-3-18
Published in Print: 2014-9-1

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