Affordable Access

Access to the full text

Botryllamide G is an ABCG2 inhibitor that improves lapatinib delivery in mouse brain

Authors
  • Strope, Jonathan D.1
  • Peer, Cody J.2
  • Sissung, Tristan M.2
  • Hall, O. Morgan2
  • Huang, Phoebe A.1
  • Harris, Emily M.1
  • Gustafson, Kirk R.3
  • Henrich, Curtis J.3, 4
  • Sigano, Dina M.5
  • Pauly, Gary T.5
  • Schneider, Joel P.5
  • Bates, Susan E.6
  • Figg, William D.1, 2
  • 1 Molecular Pharmacology Section, National Cancer Institute, USA
  • 2 Clinical Pharmacology Program, National Cancer Institute, USA
  • 3 Molecular Targets Program, National Cancer Institute, USA
  • 4 Basic Research Program, Leidos Biomedical Research Inc., Frederick National Laboratory for Cancer Research, USA
  • 5 Chemical Biology Laboratory, National Cancer Institute, USA
  • 6 Department of Medicine, Division of Hematology and Oncology, Columbia University, USA
Type
Published Article
Journal
Cancer Biology & Therapy
Publisher
Landes Bioscience
Publication Date
Nov 10, 2019
Volume
21
Issue
3
Pages
223–230
Identifiers
DOI: 10.1080/15384047.2019.1683324
PMID: 31709896
PMCID: PMC7012088
Source
PubMed Central
Keywords
License
Green

Abstract

Introduction : Transporters comprising the blood-brain barrier complicate delivery of many therapeutics to the central nervous system. The present study ascertained whether the natural product botryllamide G is viable for in vivo inhibition of ABCG2 using lapatinib as a probe for ABCB1 and ABCG2-mediated efflux from the brain. Methods : Wild-type and Mdr1a/Mdr1b (-/-) mice were treated with botryllamide G and lapatinib (“doublet therapy”), and while a separate cohort of wild-type mice was treated with botryllamide, tariquidar and lapatinib (“triplet therapy”). Results : Botryllamide G demonstrates biphasic elimination with a rapid distribution, decreasing below the in vitro IC50 of 6.9 µM within minutes, yet with a relatively slower terminal half-life (4.6 h). In Mdr1a/Mdr1b (-/-) mice, doublet therapy resulted in a significant increase in brain lapatinib AUC at 8 h (2058 h*ng/mL vs 4007 h*ng/mL; P = .031), but not plasma exposure ( P = .15). No significant differences were observed after 24 h. Lapatinib brain exposure was greater through 1 h when wild-type mice were administered triplet therapy (298 h*pg/mg vs 120 h*pg/mg; P < .001), but the triplet decreased brain AUC through 24 h vs. mice administered lapatinib alone (2878 h*pg/mg vs 4461hr*ng/mL; P < .001) and did not alter the brain:plasma ratio. Conclusions : In summary, the ABCG2 inhibitor, botryllamide G, increases brain exposure to lapatinib in mice lacking Abcb1 , although the combination of botryllamide G and tariquidar increases brain exposure in wild-type mice only briefly (1 h). Additional research is needed to find analogs of this compound that have better pharmacokinetics and pharmacodynamic effects on ABCG2 inhibition.

Report this publication

Statistics

Seen <100 times