ABCG2 C421A polymorphisms affect exposure of the epidermal growth factor receptor inhibitor gefitinib

Invest New Drugs. 2020 Dec;38(6):1687-1695. doi: 10.1007/s10637-020-00946-x. Epub 2020 May 20.


ATP-binding castle protein G2 (ABCG2) is thought to inhibit the activities of certain gefitinib transporters, thereby affecting drug pharmacokinetics. The C421A polymorphism affects the function and expression of ABCG2 on the cell membrane. Previous studies have shown that proton-pump inhibitors (PPIs) inhibit gefitinib absorption, as well as the function of ABCG2. We evaluated the plasma concentrations of gefitinib in patients with and without the ABCG2 C421A polymorphism, who were or were not taking PPIs. In total, 61 patients with advanced epidermal-growth-factor-positive non-small-cell lung cancer were enrolled in this study. They were treated with gefitinib at a dose of 250 mg per day. Plasma gefitinib concentration and ABCG2 C421A status were determined after 2 weeks. The patients were divided into CC- and CA/AA genotype groups. We compared the trough and peak gefitinib levels and the area under the curve (AUC) values for 24-h gefitinib concentrations. We also compared these parameters among four groups distinguished according to the presence or absence of the polymorphism and PPI use. The mean trough gefitinib level and AUC value for 24-h gefitinib concentration were significantly lower in the CA/AA group compared to the CC group (mean trough level: 333.2 vs. 454.5 ng/mL, respectively, P = 0.021; AUC: 9949.9 vs. 13,085.4 ng・h/mL, respectively, P = 0.034). Among patients taking PPIs, the mean trough gefitinib level was significantly lower in the CA/AA group than the CC group (220.1 vs. 340.5 ng/mL, respectively, P = 0.033). The CA/AA-type of ABCG2 C421A polymorphism may be associated with lower gefitinib plasma concentrations.

Keywords: ABCG2; EGFR mutation; Gefitinib; Non-small-cell lung cancer.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • ATP Binding Cassette Transporter, Subfamily G, Member 2 / genetics*
  • Aged
  • Aged, 80 and over
  • Antineoplastic Agents / blood
  • Antineoplastic Agents / pharmacokinetics*
  • Carcinoma, Non-Small-Cell Lung* / blood
  • Carcinoma, Non-Small-Cell Lung* / drug therapy
  • Carcinoma, Non-Small-Cell Lung* / genetics
  • Carcinoma, Non-Small-Cell Lung* / metabolism
  • ErbB Receptors / antagonists & inhibitors
  • Female
  • Gefitinib / blood
  • Gefitinib / pharmacokinetics*
  • Genotype
  • Humans
  • Lung Neoplasms* / blood
  • Lung Neoplasms* / drug therapy
  • Lung Neoplasms* / genetics
  • Lung Neoplasms* / metabolism
  • Male
  • Middle Aged
  • Neoplasm Proteins / genetics*
  • Polymorphism, Single Nucleotide
  • Protein Kinase Inhibitors / blood
  • Protein Kinase Inhibitors / pharmacokinetics*
  • Proton Pump Inhibitors / therapeutic use*


  • ABCG2 protein, human
  • ATP Binding Cassette Transporter, Subfamily G, Member 2
  • Antineoplastic Agents
  • Neoplasm Proteins
  • Protein Kinase Inhibitors
  • Proton Pump Inhibitors
  • EGFR protein, human
  • ErbB Receptors
  • Gefitinib