Display options
Cite
Jouan E, Moreau A, Bruyere A, et al. Differential Inhibition of Equilibrative Nucleoside Transporter 1 (ENT1) Activity by Tyrosine Kinase Inhibitors. Eur J Drug Metab Pharmacokinet. 2021;46(5):625-635doi: 10.1007/s13318-021-00703-2.
Jouan, E., Moreau, A., Bruyere, A., Alim, K., Denizot, C., Parmentier, Y., & Fardel, O. (2021). Differential Inhibition of Equilibrative Nucleoside Transporter 1 (ENT1) Activity by Tyrosine Kinase Inhibitors. European journal of drug metabolism and pharmacokinetics, 46(5), 625-635. https://doi.org/10.1007/s13318-021-00703-2
Jouan, Elodie, et al. "Differential Inhibition of Equilibrative Nucleoside Transporter 1 (ENT1) Activity by Tyrosine Kinase Inhibitors." European journal of drug metabolism and pharmacokinetics vol. 46,5 (2021): 625-635. doi: https://doi.org/10.1007/s13318-021-00703-2
Jouan E, Moreau A, Bruyere A, Alim K, Denizot C, Parmentier Y, Fardel O. Differential Inhibition of Equilibrative Nucleoside Transporter 1 (ENT1) Activity by Tyrosine Kinase Inhibitors. Eur J Drug Metab Pharmacokinet. 2021 Sep;46(5):625-635. doi: 10.1007/s13318-021-00703-2. Epub 2021 Jul 18. PMID: 34275128; PMCID: PMC8286641.
Copy Download .nbib Format: NLM
Share it on

Eur J Drug Metab Pharmacokinet. 2021 Sep;46(5):625-635. doi: 10.1007/s13318-021-00703-2. Epub 2021 Jul 18.

Differential Inhibition of Equilibrative Nucleoside Transporter 1 (ENT1) Activity by Tyrosine Kinase Inhibitors.

European journal of drug metabolism and pharmacokinetics

Elodie Jouan, Amélie Moreau, Arnaud Bruyere, Karima Alim, Claire Denizot, Yannick Parmentier, Olivier Fardel

Affiliations

  1. Univ Rennes, Inserm, EHESP, Irset (Institut de recherche en santé, environnement et travail), UMR_S 1085, 35000, Rennes, France.
  2. Centre de Pharmacocinétique, Technologie Servier, 45000, Orléans, France.
  3. Univ Rennes, CHU Rennes, Inserm, EHESP, Irset (Institut de recherche en santé, environnement et travail), UMR_S 1085, 35000, Rennes, France. [email protected].

PMID: 34275128 PMCID: PMC8286641 DOI: 10.1007/s13318-021-00703-2

Abstract

BACKGROUND AND OBJECTIVES: Equilibrative nucleoside transporter (ENT) 1 is a widely-expressed drug transporter, handling nucleoside analogues as well as endogenous nucleosides. ENT1 has been postulated to be inhibited by some marketed tyrosine kinase inhibitors (TKIs). To obtain insights into this point, the interactions of 24 TKIs with ENT1 activity have been analyzed.

METHODS: Inhibition of ENT1 activity was investigated in vitro through quantifying the decrease of [

RESULTS: Of 24 TKIs, 12 of them, each used at 10 µM, were found to behave as moderate or strong inhibitors of ENT1, i.e., they decreased ENT1 activity by at least 35%. This inhibition was concentration-dependent for at least the strongest ones (IC

CONCLUSION: Our data unambiguously add ENT1 to the list of drug transporters inhibited by TKIs, especially by lorlatinib. This point likely merits attention in terms of possible drug-drug interactions, notably for nucleoside analogues, whose ENT1-mediated uptake into their target cells may be hampered by co-administrated TKIs such as lorlatinib.

© 2021. The Author(s), under exclusive licence to Springer Nature Switzerland AG.

References

  1. Baldwin SA, Beal PR, Yao SY, King AE, Cass CE, Young JD. The equilibrative nucleoside transporter family, SLC29. Pflugers Arch. 2004;447:735–43. - PubMed
  2. Molina-Arcas M, Casado FJ, Pastor-Anglada M. Nucleoside transporter proteins. Curr Vasc Pharmacol. 2009;7:426–34. - PubMed
  3. Naes SM, Ab-Rahim S, Mazlan M, Abdul RA. Equilibrative Nucleoside Transporter 2: Properties and Physiological Roles. Biomed Res Int. 2020;2020:5197626. - PubMed
  4. Pastor-Anglada M, Pérez-Torras S. Nucleoside transporter proteins as biomarkers of drug responsiveness and drug targets. Front Pharmacol. 2015;6:13. - PubMed
  5. Farrell JJ, Elsaleh H, Garcia M, Lai R, Ammar A, Regine WF, Abrams R, Benson AB, Macdonald J, Cass CE, Dicker AP, Mackey JR. Human equilibrative nucleoside transporter 1 levels predict response to gemcitabine in patients with pancreatic cancer. Gastroenterology. 2009;136:187–95. - PubMed
  6. Galmarini CM, Thomas X, Calvo F, Rousselot P, Rabilloud M, El Jaffari A, Cros E, Dumontet C. In vivo mechanisms of resistance to cytarabine in acute myeloid leukaemia. Br J Haematol. 2002;117:860–8. - PubMed
  7. Spratlin J, Sangha R, Glubrecht D, Dabbagh L, Young JD, Dumontet C, Cass C, Lai R, Mackey JR. The absence of human equilibrative nucleoside transporter 1 is associated with reduced survival in patients with gemcitabine-treated pancreas adenocarcinoma. Clin Cancer Res. 2004;10:6956–61. - PubMed
  8. Endres CJ, Moss AM, Ishida K, Govindarajan R, Unadkat JD. The role of the equilibrative nucleoside transporter 1 on tissue and fetal distribution of ribavirin in the mouse. Biopharm Drug Dispos. 2016;37:336–44. - PubMed
  9. Nishimura T, Sano Y, Takahashi Y, Noguchi S, Uchida Y, Takagi A, Tanaka T, Katakura S, Nakashima E, Tachikawa M, Maruyama T, Terasaki T, Tomi M. Quantification of ENT1 and ENT2 proteins at the placental barrier and contribution of these transporters to ribavirin uptake. J Pharm Sci. 2019;108:3917–22. - PubMed
  10. Klein DM, Evans KK, Hardwick RN, Dantzler WH, Wright SH, Cherrington NJ. Basolateral uptake of nucleosides by sertoli cells is mediated primarily by equilibrative nucleoside transporter 1. J Pharmacol Exp Therap. 2013;346:121–9. - PubMed
  11. Borbone N, Piccialli G, Roviello GN, Oliviero G. Nucleoside analogs and nucleoside precursors as drugs in the fight against SARS-CoV-2 and other coronaviruses. Molecules. 2021;26:986. https://doi.org/10.3390/molecules26040986 . - PubMed
  12. Geiger JD, Khan N, Murugan M, Boison D. Possible role of adenosine in COVID-19 pathogenesis and therapeutic opportunities. Front Pharmacol. 2020;11:594487. https://doi.org/10.3389/fphar.2020.594487 . - PubMed
  13. Armstrong D, Summers C, Ewart L, Nylander S, Sidaway JE, van Giezen JJ. Characterization of the adenosine pharmacology of ticagrelor reveals therapeutically relevant inhibition of equilibrative nucleoside transporter 1. J Cardiovasc Pharmacol Ther. 2014;19:209–19. - PubMed
  14. Miller SR, Zhang X, Hau RK, Jilek JL, Jennings EQ, Galligan JJ, Foil DH, Zorn KM, Ekins S, Wright SH, Cherrington NJ. Predicting drug interactions with human equilibrative nucleoside transporters 1 and 2 using functional knockout cell lines and bayesian modeling. Mol Pharmacol. 2021;99:147–62. - PubMed
  15. Hillgren KM, Keppler D, Zur AA, Giacomini KM, Stieger B, Cass CE, Zhang L. Emerging transporters of clinical importance: an update from the International Transporter Consortium. Clin Pharmacol Ther. 2013;94:52–63. - PubMed
  16. Huang M, Wang Y, Cogut SB, Mitchell BS, Graves LM. Inhibition of nucleoside transport by protein kinase inhibitors. J Pharmacol Exp Ther. 2003;304:753–60. - PubMed
  17. Damaraju VL, Weber D, Kuzma M, Cass CE, Sawyer MB. Selective Inhibition of Human Equilibrative and Concentrative Nucleoside Transporters by BCR-ABL Kinase Inhibitors: identification of key hENT1 Amino Acid Residues For Interaction With BCR-ABL kinase inhibitors. J Biol Chem. 2016;291:18809–17. - PubMed
  18. Damaraju VL, Scriver T, Mowles D, Kuzma M, Ryan AJ, Cass CE, Sawyer MB. Erlotinib, gefitinib, and vandetanib inhibit human nucleoside transporters and protect cancer cells from gemcitabine cytotoxicity. Clin Cancer Res. 2014;20:176–86. - PubMed
  19. Damaraju VL, Kuzma M, Mowles D, Cass CE, Sawyer MB. Interactions of multitargeted kinase inhibitors and nucleoside drugs: achilles heel of combination therapy? Mol Cancer Ther. 2015;14:236–45. - PubMed
  20. Essletzbichler P, Konopka T, Santoro F, Chen D, Gapp BV, Kralovics R, Brummelkamp TR, Nijman SM, Bürckstümmer T. Megabase-scale deletion using CRISPR/Cas9 to generate a fully haploid human cell line. Genome Res. 2014;24:2059–65. - PubMed
  21. Le Vée M, Jouan E, Fardel O. Carrier-mediated uptake of clonidine in cultured human lung cells. Naunyn Schmiedebergs Arch Pharmacol. 2018;391:361–9. - PubMed
  22. Giard DJ, Aaronson SA, Todaro GJ, Arnstein P, Kersey JH, Dosik H, Parks WP. In vitro cultivation of human tumors: establishment of cell lines derived from a series of solid tumors. J Natl Cancer Inst. 1973;51:1417–23. - PubMed
  23. Mayati A, Moreau A, Jouan E, Febvre-James M, Denizot C, Parmentier Y, Fardel O. mRNA expression and activity of nucleoside transporters in human hepatoma HepaRG cells. Pharmaceutics. 2018;10:246. https://doi.org/10.3390/pharmaceutics10040246 . - PubMed
  24. Bradford MM. A rapid and sensitive method for the quantitation of microgram quantities of protein utilizing the principle of protein-dye binding. Anal Biochem. 1976;72:248–54. - PubMed
  25. In Vitro Drug Interaction Studies—Cytochrome P450 Enzyme- and Transporter-Mediated Drug Interactions Guidance for Industry, US Food and Drug Administration. https://www.fda.gov/regulatory-information/search-fda-guidance-documents/vitro-drug-interaction-studies-cytochrome-p450-enzyme-and-transporter-mediated-drug-interactions . Accessed 20 Sept 2020. - PubMed
  26. Chedik L, Bruyere A, Le Vee M, Stieger B, Denizot C, Parmentier Y, Potin S, Fardel O. Inhibition of human drug transporter activities by the pyrethroid pesticides allethrin and tetramethrin. PLoS ONE. 2017;12:e0169480. - PubMed
  27. 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. - PubMed
  28. Alim K, Moreau A, Bruyère A, Jouan E, Denizot C, Nies AT, Parmentier Y, Fardel O. Inhibition of organic cation transporter 3 activity by tyrosine kinase inhibitors. Fundam Clin Pharmacol. 2021. https://doi.org/10.1111/fcp.12657 . - PubMed
  29. Hayden E, Chen M, Pasquariello KZ, Gibson AA, Petti JJ, Shen S, Qu J, Ong SS, Chen T, Jin Y, Uddin ME, Huang KM, Paz A, Sparreboom A, Hu S, Sprowl JA. Regulation of OATP1B1 function by tyrosine kinase-mediated phosphorylation. Clin Cancer Res. 2021. https://doi.org/10.1158/1078-0432.CCR-21-0023 . - PubMed
  30. Bruyère A, Le Vée M, Jouan E, Molez S, Nies AT, Fardel O. Differential in vitro interactions of the Janus kinase inhibitor ruxolitinib with human SLC drug transporters. Xenobiotica. 2021;51:467–78. - PubMed
  31. Sprowl JA, Ong SS, Gibson AA, Hu S, Du G, Lin W, Li L, Bharill S, Ness RA, Stecula A, Offer SM, Diasio RB, Nies AT, Schwab M, Cavaletti G, Schlatter E, Ciarimboli G, Schellens JHM, Isacoff EY, Sali A, Chen T, Baker SD, Sparreboom A, Pabla N. A phosphotyrosine switch regulates organic cation transporters. Nat Commun. 2016;7:10880. - PubMed
  32. Uddin ME, Garrison DA, Kim K, Jin Y, Eisenmann ED, Huang KM, Gibson AA, Hu Z, Sparreboom A, Hu S. Influence of yes1 kinase and tyrosine phosphorylation on the activity of OCT1. Front Pharmacol. 2021;12:644342. - PubMed
  33. Johnson TW, Richardson PF, Bailey S, Brooun A, Burke BJ, Collins MR, Cui JJ, Deal JG, Deng YL, Dinh D, Engstrom LD, He M, Hoffman J, Hoffman RL, Huang Q, Kania RS, Kath JC, Lam H, Lam JL, Le PT, Lingardo L, Liu W, McTigue M, Palmer CL, Sach NW, Smeal T, Smith GL, Stewart AE, Timofeevski S, Zhu H, Zhu J, Zou HY, Edwards MP. Discovery of (10R)-7-amino-12-fluoro-2,10,16-trimethyl-15-oxo-10,15,16,17-tetrahydro-2H-8,4-(metheno)pyrazolo[4,3-h][2,5,11]-benzoxadiazacyclotetradecine-3-carbonitrile (PF-06463922), a macrocyclic inhibitor of anaplastic lymphoma kinase (ALK) and c-ros oncogene 1 (ROS1) with preclinical brain exposure and broad-spectrum potency against ALK-resistant mutations. J Med Chem. 2014;57:4720–44. - PubMed
  34. Honigberg LA, Smith AM, Sirisawad M, Verner E, Loury D, Chang B, Li S, Pan Z, Thamm DH, Miller RA, Buggy JJ. The Bruton tyrosine kinase inhibitor PCI-32765 blocks B-cell activation and is efficacious in models of autoimmune disease and B-cell malignancy. Proc Natl Acad Sci U S A. 2010;107:13075–80. - PubMed
  35. William AD, Lee AC, Blanchard S, Poulsen A, Teo EL, Nagaraj H, Tan E, Chen D, Williams M, Sun ET, Goh KC, Ong WC, Goh SK, Hart S, Jayaraman R, Pasha MK, Ethirajulu K, Wood JM, Dymock BW. Discovery of the macrocycle 11-(2-pyrrolidin-1-yl-ethoxy)-14,19-dioxa-5,7,26-triaza-tetracyclo[19.3.1.1(2,6).1(8,12)]heptacosa-1(25),2(26),3,5,8,10,12(27),16,21,23-decaene (SB1518), a potent Janus kinase 2/fms-like tyrosine kinase-3 (JAK2/FLT3) inhibitor for the treatment of myelofibrosis and lymphoma. J Med Chem. 2011;54:4638–58. - PubMed
  36. Wright NJ, Lee SY. Structures of human ENT1 in complex with adenosine reuptake inhibitors. Nat Struct Mol Biol. 2019;26:599–606. - PubMed
  37. De Bruyn T, van Westen GJ, Ijzerman AP, Stieger B, de Witte P, Augustijns PF, Annaert PP. Structure-based identification of OATP1B1/3 inhibitors. Mol Pharmacol. 2013;83:1257–67. - PubMed
  38. Liu HC, Goldenberg A, Chen Y, Lun C, Wu W, Bush KT, Balac N, Rodriguez P, Abagyan R, Nigam SK. Molecular properties of drugs interacting with SLC22 transporters OAT1, OAT3, OCT1, and OCT2: A machine-learning approach. J Pharmacol Exp Ther. 2016;359:215–29. - PubMed
  39. Wittwer MB, Zur AA, Khuri N, Kido Y, Kosaka A, Zhang X, Morrissey KM, Sali A, Huang Y, Giacomini KM. Discovery of potent, selective multidrug and toxin extrusion transporter 1 (MATE1, SLC47A1) inhibitors through prescription drug profiling and computational modeling. J Med Chem. 2013;56:781–95. - PubMed
  40. Hall LH, Kier LB. Electrotopological state indexes for atom types—a novel combination of electronic, topological, and valence state information. J Chem Inf Comput Sci. 1995;35:1039–45. - PubMed
  41. Shaw AT, Bauer TM, de Marinis F, Felip E, Goto Y, Liu G, Mazieres J, Kim DW, Mok T, Polli A, Thurm H, Calella AM, Peltz G, Solomon BJ. First-line lorlatinib or crizotinib in advanced ALK-positive lung cancer. N Engl J Med. 2020;383:2018–29. - PubMed
  42. Yuasa H, Yasujima T, Inoue K. Current understanding of the intestinal absorption of nucleobases and analogs. Biol Pharm Bull. 2020;43:1293–300. - PubMed
  43. Ibrutinib. Pharmacology review, Center for Drug Evaluation and Research, US Food and Drug Administration. https://www.accessdata.fda.gov/drugsatfda_docs/nda/2014/205552Orig2s000ClinPharmR.pdf . Accessed 15 Feb 2021. - PubMed
  44. Lenvatinib. Pharmacology review, Center for Drug Evaluation and Research, US Food and Drug Administration.  https://www.accessdata.fda.gov/drugsatfda_docs/nda/2015/206947Orig1s000ClinPharmR.pdf . Accessed 15 Feb 2021. - PubMed
  45. Lorlatinib. Pharmacology review, Center for Drug Evaluation and Research, US Food and Drug Administration.  https://www.accessdata.fda.gov/drugsatfda_docs/nda/2018/210868Orig1s000MultidisciplineR.pdf . Accessed 14 Feb 2021. - PubMed
  46. Neratinib. Label, Center for Drug Evaluation and Research, US Food and Drug Administration.  https://www.accessdata.fda.gov/drugsatfda_docs/nda/2017/208051Orig1s000MultidisciplineR.pdf . Accessed 26 Feb 2021. - PubMed
  47. Pacritinib. Assessment report, European Medecines Agency.  https://www.ema.europa.eu/en/documents/withdrawal-report/withdrawal-assessment-report-enpaxiq_en.pdf . Accessed 16 Feb 2021. - PubMed

Publication Types