Complete inhibition of ABCB1 and ABCG2 at the blood-brain barrier by co-infusion of erlotinib and tariquidar to improve brain delivery of the model ABCB1/ABCG2 substrate [¹¹C]erlotinib.

ABSTRACT: P-glycoprotein (ABCB1) and breast cancer resistance protein (ABCG2) restrict at the blood-brain barrier (BBB) the brain distribution of the majority of currently known molecularly targeted anticancer drugs. To improve brain delivery of dual ABCB1/ABCG2 substrates, both ABCB1 and ABCG2 need to be inhibited simultaneously at the BBB. We examined the feasibility of simultaneous ABCB1/ABCG2 inhibition with i.v. co-infusion of erlotinib and tariquidar by studying brain distribution of the model ABCB1/ABCG2 substrate [¹¹C]erlotinib in mice and rhesus macaques with PET. Tolerability of the erlotinib/tariquidar combination was assessed in human embryonic stem cell-derived cerebral organoids. In mice and macaques, baseline brain distribution of [¹¹C]erlotinib was low (brain di

SUBMITTER: Tournier N 

PROVIDER: S-EPMC8221757 | biostudies-literature | 2021 Jul

REPOSITORIES: biostudies-literature