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 journalArticle

2 Citations (Scopus)

Abstract

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-phenylethyl)-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: the biological fate of chemicals
Volume47
Issue number4
DOIs
StatePublished - Apr 1 2019

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Epidermal Growth Factor Receptor
Brain
Blood-Brain Barrier
Non-Small Cell Lung Carcinoma
Brain Neoplasms
P-Glycoprotein
Glioblastoma
Protein-Tyrosine Kinases
Amines
Permeability
Clinical Trials
Breast Neoplasms
Neoplasm Metastasis

ASJC Scopus subject areas

  • Pharmacology
  • Pharmaceutical Science

Cite this

Brain Distribution of a Panel of Epidermal Growth Factor Receptor Inhibitors Using Cassette Dosing in Wild-Type and Abcb1/Abcg2-Deficient Mice. / Kim, Minjee; Laramy, Janice K.; Mohammad, Afroz S.; Talele, Surabhi; Fisher, James; Sarkaria, Jann N; Elmquist, William F.

In: Drug metabolism and disposition: the biological fate of chemicals, Vol. 47, No. 4, 01.04.2019, p. 393-404.

Research output: Contribution to journalArticle

Kim, Minjee ; Laramy, Janice K. ; Mohammad, Afroz S. ; Talele, Surabhi ; Fisher, James ; Sarkaria, Jann N ; Elmquist, William F. / Brain Distribution of a Panel of Epidermal Growth Factor Receptor Inhibitors Using Cassette Dosing in Wild-Type and Abcb1/Abcg2-Deficient Mice. In: Drug metabolism and disposition: the biological fate of chemicals. 2019 ; Vol. 47, No. 4. pp. 393-404.
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