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

: 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 inhibition of ABCG2 using lapatinib as a probe for ABCB1 and ABCG2-mediated efflux from the brain. : Wild-type and (-/-) 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"). : Botryllamide G demonstrates biphasic elimination with a rapid distribution, decreasing below the IC of 6.9 µM within minutes, yet with a relatively slower terminal half-life (4.6 h). In (-/-) mice, doublet therapy resulted in a significant increase in brain lapatinib AUC at 8 h (2058 hng/mL vs 4007 hng/mL; = .031), but not plasma exposure ( = .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 hpg/mg vs 120 hpg/mg; < .001), but the triplet decreased brain AUC through 24 h vs. mice administered lapatinib alone (2878 hpg/mg vs 4461hrng/mL; < .001) and did not alter the brain:plasma ratio. : In summary, the ABCG2 inhibitor, botryllamide G, increases brain exposure to lapatinib in mice lacking , 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.