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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

Issues

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:
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Published Online: 2014-05-07 | DOI: https://doi.org/10.1515/dmdi-2014-0014

Abstract

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

References

  • 1.

    Minematsu T, Giacomini KM. Interactions of tyrosine kinase inhibitors with organic cation transporters and multidrug and toxic compound extrusion proteins. Mol Cancer Ther 2011;10:531–9.CrossrefWeb of SciencePubMedGoogle Scholar

  • 2.

    Giacomini KM, Huang SM, Tweedie DJ, Benet LZ, Brouwer KL, Chu X, et al. Membrane transporters in drug development. Nat Rev Drug Discov 2010;9:215–36.CrossrefPubMedWeb of ScienceGoogle Scholar

  • 3.

    Hartmann JT, Haap M, Kopp HG, Lipp HP. Tyrosine kinase inhibitors – a review on pharmacology, metabolism and side effects. Curr Drug Metab 2009;10:470–81.CrossrefWeb of SciencePubMedGoogle Scholar

  • 4.

    Undevia SD, Gomez-Abuin G, Ratain MJ. Pharmacokinetic variability of anticancer agents. Nat Rev Cancer 2005;5:447–58.CrossrefPubMedGoogle Scholar

  • 5.

    Zimmerman EI, Hu S, Roberts JL, Gibson AA, Orwick SJ, Li L, et al. Contribution of OATP1B1 and OATP1B3 to the disposition of sorafenib and sorafenib-glucuronide. Clin Cancer Res 2013;19:1458–66.Web of ScienceCrossrefGoogle Scholar

  • 6.

    van Erp NP, Gelderblom H, Guchelaar HJ. Clinical pharmacokinetics of tyrosine kinase inhibitors. Cancer Treat Rev 2009;35:692–706.PubMedCrossrefGoogle Scholar

  • 7.

    Teo YL, Ho HK, Chan A. Risk of tyrosine kinase inhibitors-induced hepatotoxicity in cancer patients: a meta-analysis. Cancer Treat Rev 2013;39:199–206.PubMedCrossrefGoogle Scholar

  • 8.

    Xu CF, Reck BH, Xue Z, Huang L, Baker KL, Chen M, et al. Pazopanib-induced hyperbilirubinemia is associated with Gilbert’s syndrome UGT1A1 polymorphism. Br J Cancer 2010;102: 1371–7.CrossrefGoogle Scholar

  • 9.

    Sternberg CN, Davis ID, Mardiak J, Szczylik C, Lee E, Wagstaff J, et al. Pazopanib in locally advanced or metastatic renal cell carcinoma: results of a randomized phase III trial. J Clin Oncol 2010;28:1061–8.CrossrefPubMedGoogle Scholar

  • 10.

    Swift B, Nebot N, Lee JK, Han T, Proctor WR, Thakker DR, et al. Sorafenib hepatobiliary disposition: mechanisms of hepatic uptake and disposition of generated metabolites. Drug Metab Dispos 2013;41:1179–86.PubMedWeb of ScienceCrossrefGoogle Scholar

  • 11.

    Hu S, Franke RM, Filipski KK, Hu C, Orwick SJ, de Bruijn EA, et al. Interaction of imatinib with human organic ion carriers. Clin Cancer Res 2008;14:3141–8.CrossrefWeb of ScienceGoogle Scholar

  • 12.

    Minocha M, Khurana V, Qin B, Pal D, Mitra AK. Enhanced brain accumulation of pazopanib by modulating P-gp and Bcrp1 mediated efflux with canertinib or erlotinib. Int J Pharm 2012;436:127–34.Web of ScienceGoogle Scholar

  • 13.

    Minocha M, Khurana V, Qin B, Pal D, Mitra AK. Co-administration strategy to enhance brain accumulation of vandetanib by modulating P-glycoprotein (P-gp/Abcb1) and breast cancer resistance protein (Bcrp1/Abcg2) mediated efflux with m-TOR inhibitors. Int J Pharm 2012;434:306–14.Web of ScienceGoogle Scholar

  • 14.

    Khurana V, Minocha M, Pal D, Mitra AK. Role of OATP-1B1 and/or OATP-1B3 in hepatic disposition of tyrosine kinase inhibitors. Drug Metab Drug Interact 2014. Epub ahead of print. doi: 10.1515/dmdi-2013-0062.CrossrefGoogle Scholar

  • 15.

    Karlgren M, Vildhede A, Norinder U, Wisniewski JR, Kimoto E, Lai Y, et al. Classification of inhibitors of hepatic organic anion transporting polypeptides (OATPs): influence of protein expression on drug-drug interactions. J Med Chem 2012;55:4740–63.CrossrefPubMedWeb of ScienceGoogle Scholar

  • 16.

    Shitara Y. Clinical importance of OATP1B1 and OATP1B3 in drug-drug interactions. Drug Metab Pharmacokinet 2011;26:220–7.CrossrefWeb of ScienceGoogle Scholar

  • 17.

    Kumar R, Knick VB, Rudolph SK, Johnson JH, Crosby RM, Crouthamel MC, et al. Pharmacokinetic-pharmacodynamic correlation from mouse to human with pazopanib, a multikinase angiogenesis inhibitor with potent antitumor and antiangiogenic activity. Mol Cancer Ther 2007;6:2012–21.CrossrefPubMedGoogle Scholar

  • 18.

    Hu S, Niu H, Inaba H, Orwick S, Rose C, Panetta JC, et al. Activity of the multikinase inhibitor sorafenib in combination with cytarabine in acute myeloid leukemia. J Natl Cancer Inst 2011;103:893–905.PubMedWeb of ScienceCrossrefGoogle Scholar

  • 19.

    Kalliokoski A, Niemi M. Impact of OATP transporters on pharmacokinetics. Br J Pharmacol 2009;158:693–705.Web of ScienceGoogle Scholar

  • 20.

    Konig J, Cui Y, Nies AT, Keppler D. Localization and genomic organization of a new hepatocellular organic anion transporting polypeptide. J Biol Chem 2000;275:23161–8.Google Scholar

  • 21.

    De Bruyn T, van Westen GJ, Ijzerman AP, Stieger B, de Witte P, Augustijns PF, et al. Structure-based identification of OATP1B1/3 inhibitors. Mol Pharmacol 2013;83:1257–67.CrossrefGoogle Scholar

  • 22.

    Gui C, Obaidat A, Chaguturu R, Hagenbuch B. Development of a cell-based high-throughput assay to screen for inhibitors of organic anion transporting polypeptides 1B1 and 1B3. Curr Chem Genomics 2010;4:1–8.CrossrefPubMedGoogle Scholar

  • 23.

    Nozawa T, Minami H, Sugiura S, Tsuji A, Tamai I. Role of organic anion transporter OATP1B1 (OATP-C) in hepatic uptake of irinotecan and its active metabolite, 7-ethyl-10-hydroxycamptothecin: in vitro evidence and effect of single nucleotide polymorphisms. Drug Metab Dispos 2005;33:434–9.Google Scholar

  • 24.

    Hu S, Mathijssen RH, de Bruijn P, Baker SD, Sparreboom A. Inhibition of OATP1B1 by tyrosine kinase inhibitors: in vitro-in vivo correlations. Br J Cancer 2014;110:894–8.CrossrefGoogle Scholar

  • 25.

    Hagenbuch B, Meier PJ. The superfamily of organic anion transporting polypeptides. Biochim Biophys Acta 2003;1609:1–18.Google Scholar

  • 26.

    Hagenbuch B, Meier PJ. Organic anion transporting polypeptides of the OATP/SLC21 family: phylogenetic classification as OATP/SLCO superfamily, new nomenclature and molecular/functional properties. Pflugers Arch 2004;447:653–65.Google Scholar

  • 27.

    Smith NF, Figg WD, Sparreboom A. Role of the liver-specific transporters OATP1B1 and OATP1B3 in governing drug elimination. Expert Opin Drug Metab Toxicol 2005;1:429–45.CrossrefGoogle Scholar

  • 28.

    Abe T, Unno M, Onogawa T, Tokui T, Kondo TN, Nakagomi R, et al. LST-2, a human liver-specific organic anion transporter, determines methotrexate sensitivity in gastrointestinal cancers. Gastroenterology 2001;120:1689–99.PubMedCrossrefGoogle Scholar

  • 29.

    Muto M, Onogawa T, Suzuki T, Ishida T, Rikiyama T, Katayose Y, et al. Human liver-specific organic anion transporter-2 is a potent prognostic factor for human breast carcinoma. Cancer Sci 2007;98:1570–6.PubMedCrossrefGoogle Scholar

  • 30.

    Smith NF, Acharya MR, Desai N, Figg WD, Sparreboom A. Identification of OATP1B3 as a high-affinity hepatocellular transporter of paclitaxel. Cancer Biol Ther 2005;4:815–8.CrossrefPubMedGoogle Scholar

  • 31.

    de Graan AJ, Lancaster CS, Obaidat A, Hagenbuch B, Elens L, Friberg LE, et al. Influence of polymorphic OATP1B-type carriers on the disposition of docetaxel. Clin Cancer Res 2012;18: 4433–40.CrossrefWeb of ScienceGoogle Scholar

  • 32.

    Yamazaki M, Suzuki H, Sugiyama Y. Recent advances in carrier-mediated hepatic uptake and biliary excretion of xenobiotics. Pharm Res 1996;13:497–513.CrossrefPubMedGoogle Scholar

  • 33.

    Shitara Y, Horie T, Sugiyama Y. Transporters as a determinant of drug clearance and tissue distribution. Eur J Pharm Sci 2006;27:425–46.PubMedCrossrefGoogle Scholar

  • 34.

    Asberg A, Hartmann A, Fjeldsa E, Bergan S, Holdaas H. Bilateral pharmacokinetic interaction between cyclosporine A and atorvastatin in renal transplant recipients. Am J Transplant 2001;1:382–6.PubMedCrossrefGoogle Scholar

  • 35.

    Hedman M, Neuvonen PJ, Neuvonen M, Holmberg C, Antikainen M. Pharmacokinetics and pharmacodynamics of pravastatin in pediatric and adolescent cardiac transplant recipients on a regimen of triple immunosuppression. Clin Pharmacol Ther 2004;75:101–9.PubMedCrossrefGoogle Scholar

  • 36.

    Nakagomi-Hagihara R, Nakai D, Tokui T, Abe T, Ikeda T. Gemfibrozil and its glucuronide inhibit the hepatic uptake of pravastatin mediated by OATP1B1. Xenobiotica 2007;37:474–86.Web of ScienceCrossrefGoogle Scholar

  • 37.

    Kyrklund C, Backman JT, Neuvonen M, Neuvonen PJ. Gemfibrozil increases plasma pravastatin concentrations and reduces pravastatin renal clearance. Clin Pharmacol Ther 2003;73: 538–44.PubMedCrossrefGoogle Scholar

  • 38.

    Whitfield LR, Porcari AR, Alvey C, Abel R, Bullen W, Hartman D. Effect of gemfibrozil and fenofibrate on the pharmacokinetics of atorvastatin. J Clin Pharmacol 2011;51:378–88.PubMedWeb of ScienceCrossrefGoogle Scholar

  • 39.

    Shitara Y, Maeda K, Ikejiri K, Yoshida K, Horie T, Sugiyama Y. Clinical significance of organic anion transporting polypeptides (OATPs) in drug disposition: their roles in hepatic clearance and intestinal absorption. Biopharm Drug Dispos 2013;34:45–78.Web of SciencePubMedCrossrefGoogle Scholar

  • 40.

    Kim RB. Organic anion-transporting polypeptide (OATP) transporter family and drug disposition. Eur J Clin Invest 2003;33:Suppl 2:1–5.CrossrefPubMedGoogle Scholar

  • 41.

    Tan AR, Dowlati A, Jones SF, Infante JR, Nishioka J, Fang L, et al. Phase I study of pazopanib in combination with weekly paclitaxel in patients with advanced solid tumors. Oncologist 2010;15:1253–61.PubMedCrossrefWeb of ScienceGoogle Scholar

  • 42.

    Jang SH, Wientjes MG, Au JL. Kinetics of P-glycoprotein-mediated efflux of paclitaxel. J Pharmacol Exp Ther 2001;298:1236–42.Google Scholar

  • 43.

    Kemper EM, van Zandbergen AE, Cleypool C, Mos HA, Boogerd W, Beijnen JH, et al. Increased penetration of paclitaxel into the brain by inhibition of P-Glycoprotein. Clin Cancer Res 2003;9:2849–55.PubMedGoogle Scholar

  • 44.

    Fahrmayr C, Fromm MF, Konig J. Hepatic OATP and OCT uptake transporters: their role for drug-drug interactions and pharmacogenetic aspects. Drug Metab Rev 2010;42:380–401.CrossrefPubMedGoogle Scholar

  • 45.

    Singer JB, Shou Y, Giles F, Kantarjian HM, Hsu Y, Robeva AS, et al. UGT1A1 promoter polymorphism increases risk of nilotinib-induced hyperbilirubinemia. Leukemia 2007;21:2311–5.CrossrefWeb of ScienceGoogle Scholar

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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