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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

Editorial Board Member: Benjeddou, Mongi / Chen, Bing / Dahl, Marja-Liisa / Devinsky, Ferdinand / Hirata, Rosario D. C. / 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.

SCImago Journal Rank (SJR) 2015: 0.447
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Inhibition of OATP-1B1 and OATP-1B3 by tyrosine kinase inhibitors

Varun Khurana1, 2 / Mukul Minocha1, 3 / Dhananjay Pal1 / 1

1Division of Pharmaceutical Sciences, School of Pharmacy, University of Missouri-Kansas City, 2464 Charlotte Street, Kansas City, MO 64108-2718, USA

2INSYS Therapeutics Inc, 444 South Ellis Road, Chandler, AZ 85224, USA

3Center for Translational Medicine, School of Pharmacy, University of Maryland Baltimore, 20 North Pine Street, Baltimore, MD 21201, USA

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:

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

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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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