Nilotinib Alters the Efflux Transporter-Mediated Pharmacokinetics of Afatinib in Mice

J Pharm Sci. 2019 Oct;108(10):3434-3442. doi: 10.1016/j.xphs.2019.05.028. Epub 2019 Jun 1.


Small-molecule tyrosine kinase inhibitors (TKIs) are novel anticancer agents with enhanced selectivity and superior safety profiles than conventional chemotherapeutics. A major shortcoming in TKI therapy is the development of acquired resistance. An important resistance mechanism is reduced intracellular drug accumulation due to an overexpression of efflux transporters such as P-glycoprotein (Pgp) and breast cancer resistance protein (BCRP) in cancer cells. TKIs have dual roles as substrates and inhibitors of Pgp and BCRP; thus, combination TKI therapy could potentially reverse efflux transporter-mediated TKI resistance. In the present study, the effect of 14 TKIs on Pgp-, Bcrp1-, and BCRP-mediated afatinib efflux was investigated in vitro. Nilotinib was a potent inhibitor of Pgp, Bcrp1, and BCRP, with EC50 values of 2.22, 2.47, and 0.692 μM, respectively. Consequently, the pharmacokinetics of afatinib with and without the coadministration of nilotinib was determined in mice plasma and various tissues. Nilotinib increased afatinib AUC by 188% in plasma, and this altered tissue AUC by -38.8% to +221%. Nilotinib also decreased the clearance of afatinib by 65.3%, from 609 to 211 mL/h. Further studies are warranted to assess nilotinib's chemosensitizing effect in tumor xenograft models.

Keywords: P-glycoprotein; breast cancer resistance protein; combination therapy; efflux pumps; pharmacokinetics; tyrosine kinase inhibitors.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Afatinib / pharmacokinetics*
  • Animals
  • Antineoplastic Agents / pharmacokinetics*
  • Biological Transport / physiology
  • Cell Line
  • Dogs
  • Humans
  • Madin Darby Canine Kidney Cells
  • Male
  • Membrane Transport Proteins / metabolism*
  • Mice
  • Protein Kinase Inhibitors / pharmacokinetics*
  • Protein-Tyrosine Kinases / metabolism
  • Pyrimidines / pharmacology*
  • Swine


  • Antineoplastic Agents
  • Membrane Transport Proteins
  • Protein Kinase Inhibitors
  • Pyrimidines
  • Afatinib
  • Protein-Tyrosine Kinases
  • nilotinib