Brain accumulation of sunitinib is restricted by P-glycoprotein (ABCB1) and breast cancer resistance protein (ABCG2) and can be enhanced by oral elacridar and sunitinib coadministration

摘要: Sunitinib is an orally active, multitargeted tyrosine kinase inhibitor which has been used for the treatment of metastatic renal cell carcinoma and imatinib-resistant gastrointestinal stromal tumors. We aimed to investigate in vivo roles ATP-binding cassette drug efflux transporters ABCB1 ABCG2 plasma pharmacokinetics brain accumulation oral sunitinib, feasibility improving sunitinib kinetics using coadministration dual ABCB1/ABCG2 elacridar. vitro transport assays Abcb1a/1b−/−, Abcg2−/− Abcb1a/1b/Abcg2−/− mice study disposition. In vitro, was a good substrate murine (mu)ABCG2 moderate human (hu)ABCB1 huABCG2. vivo, systemic exposure after dosing (10 mg kg−1) unchanged when muABCB1 and/or muABCG2 were absent. Brain markedly (23-fold) increased Abcb1a/b/Abcg2−/− mice, but only slightly (2.3-fold) Abcb1a/b−/− not mice. Importantly, clinically realistic elacridar wild-type resulted accumulation, equaling levels This indicates complete inhibition blood-brain barrier (BBB) transporters. High-dose intravenous could saturate BBB muABCG2, muABCB1A, illustrating dose-dependent relative impact effectively restricted by both activity. Complete transporters, leading feasible safe with elacridar/sunitinib coadministration.