Back to Search
Start Over
Botryllamide G is an ABCG2 inhibitor that improves lapatinib delivery in mouse brain.
- Source :
- Cancer Biology & Therapy; 2020, Vol. 21 Issue 3, p223-230, 8p
- Publication Year :
- 2020
-
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 IC<subscript>50</subscript> 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. [ABSTRACT FROM AUTHOR]
- Subjects :
- CENTRAL nervous system
BLOOD-brain barrier
LAPATINIB
NATURAL products
Subjects
Details
- Language :
- English
- ISSN :
- 15384047
- Volume :
- 21
- Issue :
- 3
- Database :
- Complementary Index
- Journal :
- Cancer Biology & Therapy
- Publication Type :
- Academic Journal
- Accession number :
- 141718149
- Full Text :
- https://doi.org/10.1080/15384047.2019.1683324