Skip to main content

Advertisement

SpringerLink
Log in

Binding of gefitinib, an inhibitor of epidermal growth factor receptor-tyrosine kinase, to plasma proteins and blood cells: in vitro and in cancer patients

  • Preclinical Studies
  • Published:
Investigational New Drugs Aims and scope Submit manuscript

Summary

Gefitinib exhibits wide inter-subject pharmacokinetic variability which may contribute to differences in treatment outcome. Unbound drug concentrations are believed to be more relevant to pharmacological and toxicological responses than total drug. Thus it is desirable to determine gefitinib binding in plasma and factors affecting this process. An equilibrium dialysis method using 96-well microdialysis plates was optimized and validated for determining the fraction unbound (fu) gefitinib in human plasma. Gefitinib binding in plasma from four different species and isolated protein solutions as well as drug partitioning in human blood cells were investigated. Unbound gefitinib plasma concentrations were measured in 21 cancer patients receiving daily oral gefitinib 250 mg or 500 mg. It was found that gefitinib was extensively bound in human rat mouse and dog plasma with mean fu values of 3.4%, 3.8%, 5.1% and 6.0% respectively. In isolated protein solutions approximately 90% and 78% of gefitinib was bound to human serum albumin (HSA) (40 mg/dL) and alpha1-acid glycoprotein (AAG) (1.4 mg/dL) with binding constants of 1.85 × 104 M−1 and 1.13 × 105 M−1 respectively. In whole blood 2.8% of gefitinib existed as the free drug while 79.4% and 17.8% was bound to plasma proteins and blood cells respectively. In plasma from cancer patients fu at pre-treatment varied 2.4-fold (mean 3.4 ± 0.6%; range 2.2–5.4%) and fu was constant over the 28-days of treatment (P > 0.05). Pre-treatment AAG concentration was negatively correlated with pre-treatment fu (R2 = 0.28, P = 0.01). In conclusion gefitinib is highly protein bound (∼97%) in human plasma. Variable AAG concentrations observed in cancer patients may affect gefitinib fu with implications for inter-subject variation in drug toxicity and response.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

References

  1. Baselga J and Averbuch SD: ZD1839 (’Iressa’ as an anticancer agent. Drugs 60 Suppl 1:33–0; discussion 41–2, 2000

  2. Raymond E, Faivre S, Armand JP: Epidermal growth factor receptor tyrosine kinase as a target for anticancer therapy. Drugs 60 Suppl 1:15–3; discussion 41–2, 2000

    Google Scholar 

  3. Woodburn JR: The epidermal growth factor receptor and its inhibition in cancer therapy. Pharmacol Ther 82:241–50, 1999

    Article  CAS  PubMed  Google Scholar 

  4. Anderson NG, Ahmad T, Chan K, Dobson R, Bundred NJ: ZD1839 (Iressa) a novel epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor potently inhibits the growth of EGFR-positive cancer cell lines with or without erbB2 overexpression. Int J Cancer 94:774–82, 2001

    Article  CAS  PubMed  Google Scholar 

  5. Ciardiello F, Caputo R, Bianco R, Damiano V, Fontanini G, Cuccato S, De Placido S, Bianco AR, Tortora G: Inhibition of growth factor production and angiogenesis in human cancer cells by ZD1839 (Iressa) a selective epidermal growth factor receptor tyrosine kinase inhibitor. Clin Cancer Res 7:1459–465, 2001

    CAS  PubMed  Google Scholar 

  6. Fukuoka M, Yano S, Giaccone G, Tamura T, Nakagawa K, Douillard JY, Nishiwaki Y, Vansteenkiste J, Kudoh S, Rischin D, Eek R, Horai T, Noda K, Takata I, Smit E, Averbuch S, Macleod A, Feyereislova A, Dong RP, Baselga J: Multi-institutional randomized phase II trial of gefitinib for previously treated patients with advanced non-small-cell lung cancer (The IDEAL 1 Trial) [corrected]. J Clin Oncol 21:2237–246, 2003

    Article  CAS  PubMed  Google Scholar 

  7. Kris MG, Natale RB, Herbst RS, Lynch TJ Jr, Prager D, Belani CP, Schiller JH, Kelly K, Spiridonidis H, Sandler A, Albain KS, Cella D, Wolf MK, Averbuch SD, Ochs JJ, Kay AC: Efficacy of gefitinib an inhibitor of the epidermal growth factor receptor tyrosine kinase in symptomatic patients with non-small cell lung cancer: a randomized trial. JAMA 290:2149–158, 2003

    Article  CAS  PubMed  Google Scholar 

  8. Janne PA, Engelman JA, Johnson BE: Epidermal growth factor receptor mutations in non-small-cell lung cancer: implications for treatment and tumor biology. J Clin Oncol 23:3227–234, 2005

    Article  CAS  PubMed  Google Scholar 

  9. Pao W, Miller VA: Epidermal growth factor receptor mutations small-molecule kinase inhibitors and non-small-cell lung cancer: current knowledge and future directions. J Clin Oncol 23:2556–568, 2005

    Article  CAS  PubMed  Google Scholar 

  10. Lynch TJ, Bell DW, Sordella R, Gurubhagavatula S, Okimoto RA, Brannigan BW, Harris PL, Haserlat SM, Supko JG, Haluska FG, Louis DN, Christiani DC, Settleman J, Haber DA: Activating mutations in the epidermal growth factor receptor underlying responsiveness of non-small-cell lung cancer to gefitinib. N Engl J Med 350:2129–139, 2004

    Article  CAS  PubMed  Google Scholar 

  11. Paez JG, Janne PA, Lee JC, Tracy S, Greulich H, Gabriel S, Herman P, Kaye FJ, Lindeman N, Boggon TJ, Naoki K, Sasaki H, Fujii Y, Eck MJ, Sellers WR, Johnson BE, Meyerson M: EGFR mutations in lung cancer: correlation with clinical response to gefitinib therapy. Science 304:1497–500, 2004

    Article  CAS  PubMed  Google Scholar 

  12. Pao W, Miller V, Zakowski M, Doherty J, Politi K, Sarkaria I, Singh B, Heelan R, Rusch V, Fulton L, Mardis E, Kupfer D, Wilson R, Kris M, Varmus H: EGF receptor gene mutations are common in lung cancers from “never smokers” and are associated with sensitivity of tumors to gefitinib and erlotinib. Proc Natl Acad Sci U S A 101:13306–3311, 2004

    Article  CAS  PubMed  Google Scholar 

  13. Li J, Karlsson MO, Brahmer J, Cusatis G, Hidalgo M, Baker SD: Population pharmacokinetic (PK)-pharmacodynamic (PD) model for gefitinib in cancer patients (Abstract). Proc Amer Soc Clin Oncol 23:3083, 2005

    Google Scholar 

  14. Baker SD, Zhao M, He P, Carducci MA, Verweij J, Sparreboom A: Simultaneous analysis of docetaxel and the formulation vehicle polysorbate 80 in human plasma by liquid chromatography/tandem mass spectrometry. Anal Biochem 324:276–84, 2004

    Article  CAS  PubMed  Google Scholar 

  15. Urien S, Bastian G, Lucas C, Bizzari JP, Tillement JP: Binding of a new vinca alkaloid derivative S12363 to human plasma proteins and platelets. Usefulness of an erythrocyte partitioning technique. Invest New Drugs 10:263–68, 1992

    Article  CAS  PubMed  Google Scholar 

  16. Zhao M, Hartke C, Jimeno A, Li J, He P, Zabelina Y, Hidalgo M, Baker SD: Specific method for determination of gefitinib in human plasma mouse plasma and tissues using high performance liquid chromatography coupled to tandem mass spectrometry. J Chromatogr B Analyt Technol Biomed Life Sci 819:73–0, 2005

    Google Scholar 

  17. Combes O, Barre J, Duche JC, Vernillet L, Archimbaud Y, Marietta MP, Tillement JP, Urien S: In vitro binding and partitioning of irinotecan (CPT-11) and its metabolite SN-38 in human blood. Invest New Drugs 18:1–, 2000

    Article  CAS  PubMed  Google Scholar 

  18. Rowland M, Tozer T: Blood-to-plasma concentration ratio. In: M. Rowland and T. Tozer (eds.) Clinical Pharmacokinetics: Concepts and Applications. Williams and Wilkins, Philadelphia, 1995, pp. 502–03

    Google Scholar 

  19. Sparreboom A, Nooter K, Loos WJ, Verweij J: The (ir)relevance of plasma protein binding of anticancer drugs. Neth J Med 59:196–07, 2001

    Article  CAS  PubMed  Google Scholar 

  20. Kuchimanchi KR, Ahmed MS, Johnston TP, Mitra AK: Binding of cosalane–a novel highly lipophilic anti-HIV agent–to albumin and glycoprotein. J Pharm Sci 90:659–66, 2001

    Article  CAS  PubMed  Google Scholar 

  21. Wanwimolruk S, Denton JR: Plasma protein binding of quinine: binding to human serum albumin alpha 1-acid glycoprotein and plasma from patients with malaria. J Pharm Pharmacol 44:806–11, 1992

    CAS  PubMed  Google Scholar 

  22. Arredondo G, Calvo R, Marcos F, Martinez-Jorda R, Suarez E: Protein binding of itraconazole and fluconazole in patients with cancer. Int J Clin Pharmacol Ther 33:449–52, 1995

    CAS  PubMed  Google Scholar 

  23. Kremer JM, Wilting J, Janssen LH: Drug binding to human alpha-1-acid glycoprotein in health and disease. Pharmacol Rev 40:1–7, 1988

    CAS  PubMed  Google Scholar 

  24. Baker SD, van Schaik RH, Rivory LP, Ten Tije AJ, Dinh K, Graveland WJ, Schenk PW, Charles KA, Clarke SJ, Carducci MA, McGuire WP, Dawkins F, Gelderblom H, Verweij J, Sparreboom A: Factors affecting cytochrome P-450 3A activity in cancer patients. Clin Cancer Res 10:8341–350, 2004

    Article  CAS  PubMed  Google Scholar 

  25. Gambacorti-Passerini C, Barni R, le Coutre P, Zucchetti M, Cabrita G, Cleris L, Rossi F, Gianazza E, Brueggen J, Cozens R, Pioltelli P, Pogliani E, Corneo G, Formelli F, D’Incalci M: Role of alpha1 acid glycoprotein in the in vivo resistance of human BCR-ABL(+) leukemic cells to the abl inhibitor STI571. J Natl Cancer Inst 92:1641–650, 2000

    Article  CAS  PubMed  Google Scholar 

  26. Fuse E, Tanii H, Kurata N, Kobayashi H, Shimada Y, Tamura T, Sasaki Y, Tanigawara Y, Lush RD, Headlee D, Figg WD, Arbuck SG, Senderowicz AM, Sausville EA, Akinaga S, Kuwabara T, Kobayashi S: Unpredicted clinical pharmacology of UCN-01 caused by specific binding to human alpha1-acid glycoprotein. Cancer Res 58:3248–253, 1998

    CAS  PubMed  Google Scholar 

  27. Fuse E, Tanii H, Takai K, Asanome K, Kurata N, Kobayashi H, Kuwabara T, Kobayashi S, Sugiyama Y: Altered pharmacokinetics of a novel anticancer drug UCN-01 caused by specific high affinity binding to alpha1-acid glycoprotein in humans. Cancer Res 59:1054–060, 1999

    CAS  PubMed  Google Scholar 

  28. Gambacorti-Passerini C, Zucchetti M, Russo D, Frapolli R, Verga M, Bungaro S, Tornaghi L, Rossi F, Pioltelli P, Pogliani E, Alberti D, Corneo G, D’Incalci M: Alpha1 acid glycoprotein binds to imatinib (STI571) and substantially alters its pharmacokinetics in chronic myeloid leukemia patients. Clin Cancer Res 9:625–32, 2003

    CAS  PubMed  Google Scholar 

  29. Loos WJ, Baker SD, Verweij J, Boonstra JG, Sparreboom A: Clinical pharmacokinetics of unbound docetaxel: Role of polysorbate 80 and serum proteins. Clin Pharmacol Ther 74:364–71, 2003

    Article  CAS  PubMed  Google Scholar 

  30. van Zuylen L, Karlsson MO, Verweij J, Brouwer E, de Bruijn P, Nooter K, Stoter G, Sparreboom A: Pharmacokinetic modeling of paclitaxel encapsulation in Cremophor EL micelles. Cancer Chemother Pharmacol 47:309–18, 2001

    Article  PubMed  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore, MD

    Jing Li, Julie Brahmer, Wells Messersmith, Manuel Hidalgo & Sharyn D. Baker

  2. The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore, MD, 21211

    Sharyn D. Baker

Authors
  1. Jing Li
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Julie Brahmer
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Wells Messersmith
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Manuel Hidalgo
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Sharyn D. Baker
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Sharyn D. Baker.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Li, J., Brahmer, J., Messersmith, W. et al. Binding of gefitinib, an inhibitor of epidermal growth factor receptor-tyrosine kinase, to plasma proteins and blood cells: in vitro and in cancer patients. Invest New Drugs 24, 291–297 (2006). https://doi.org/10.1007/s10637-006-5269-2

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s10637-006-5269-2

Keywords

Search

Navigation