Brain distribution of a panel of epidermal growth factor receptor inhibitors using cassette dosing in wild-type and ABCB1/ABCG2-deficient mice

Minjee Kim, Janice K. Laramy, Afroz S. Mohammad, Surabhi Talele, James Fisher, Jann N. Sarkaria, William F. Elmquist

Research output: Contribution to journalArticlepeer-review

38 Scopus citations


Tyrosine kinase inhibitors that target the epidermal growth factor receptor (EGFR) have had success in treating EGFR-positive tumors, including non-small-cell lung cancer (NSCLC). However, developing EGFR inhibitors that can be delivered to the brain remains a challenge. To identify optimal compounds for brain delivery, eight EGFR inhibitors [afatinib, 6-[4-[(4-ethylpiperazin-1-yl)methyl]phenyl]-N-(1-phenyl-ethyl)-7H-pyrrolo[2,3-day]pyrimidin-4-amine (AEE788), [4-(3-chloro-2-fluoroanilino)-7-methoxyquinazolin-6-yl] (2R)-2,4-dimethylpiperazine-1-carboxylate (AZD3759), erlotinib, dacomitinib, gefitinib, osimertinib, and vandetanib] were evaluated for distributional kinetics using cassette dosing with the ultimate goal of understanding the brain penetrability of compounds that share the same molecular target in an important oncogenic signaling pathway for both primary brain tumors (glioblastoma) and brain metastases (e.g., NSCLC). Cassette dosing was validated by comparing the brain-to-plasma ratios obtained from cassette-dosing to discrete-dosing studies. The brain-to-blood partition coefficients (Kp,brain) were calculated following cassette dosing of the eight EGFR inhibitors. The comparison of Kp,brain in wild-type and transporter-deficient mice confirmed that two major efflux transporters at the blood-brain barrier (BBB), P-glycoprotein and breast cancer resistance protein, play a crucial role in the brain distribution of seven out of eight EGFR inhibitors. Results show that the prediction of brain distribution based on physicochemical properties of a drug can be misleading, especially for compounds subject to extensive efflux transport. Moreover, this study informs the choice of EGFR inhibitors, i.e., determining BBB permeability combined with a known target potency, that may be effective in future clinical trials for brain tumors.

Original languageEnglish (US)
Pages (from-to)393-404
Number of pages12
JournalDrug Metabolism and Disposition
Issue number4
StatePublished - Apr 2019

Bibliographical note

Funding Information:
This work was supported by the National Institutes of Health [Grants RO1 CA138437, RO1 NS077921, U54 CA210181, U01 CA227954, and P50 CA108960]. s This article has supplemental material available at

Publisher Copyright:
Copyright © 2019 by The American Society for Pharmacology and Experimental Therapeutics.


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