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

  • 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
Published Article
Cancer Biology & Therapy
Landes Bioscience
Publication Date
Nov 10, 2019
DOI: 10.1080/15384047.2019.1683324
PMID: 31709896
PMCID: PMC7012088
PubMed Central


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.

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