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

Jonathan D. Strope, Cody J. Peer, Tristan M. Sissung, O. Morgan Hall, Phoebe A. Huang, Emily M. Harris, Kirk R. Gustafson, Curtis J. Henrich, Dina M. Sigano, Gary T. Pauly, Joel P. Schneider, Susan E. Bates, William D. Figg*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

10 Scopus citations

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.

Original languageEnglish
Pages (from-to)223-230
Number of pages8
JournalCancer Biology and Therapy
Volume21
Issue number3
DOIs
StatePublished - 3 Mar 2020
Externally publishedYes

Keywords

  • ABCB1
  • ABCG2
  • Botryllamide G
  • blood brain barrier
  • lapatinib

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