Assessing the Functional Redundancy between P-gp and BCRP in Controlling the Brain Distribution and Biliary Excretion of Dual Substrates with PET Imaging in Mice

P-glycoprotein (P-gp) and breast cancer resistance protein (BCRP) are co-localized at the blood–brain barrier, where they display functional redundancy to restrict the brain distribution of dual P-gp/BCRP substrate drugs. We used positron emission tomography (PET) with the metabolically stable P-gp/BCRP substrates [(11)C]tariquidar, [(11)C]erlotinib, and [(11)C]elacridar to assess whether a similar functional redundancy as at the BBB exists in the liver, where both transporters mediate the biliary excretion of drugs. Wild-type, Abcb1a/b((−/−)), Abcg2((−/−)), and Abcb1a/b((−/−))Abcg2((−/−)) mice underwent dynamic whole-body PET scans after i.v. injection of either [(11)C]tariquidar, [(11)C]erlotinib, or [(11)C]elacridar. Brain uptake of all three radiotracers was markedly higher in Abcb1a/b((−/−))Abcg2((−/−)) mice than in wild-type mice, while only moderately changed in Abcb1a/b((−/−)) and Abcg2((−/−)) mice. The transfer of radioactivity from liver to excreted bile was significantly lower in Abcb1a/b((−/−))Abcg2((−/−)) mice and almost unchanged in Abcb1a/b((−/−)) and Abcg2((−/−)) mice (with the exception of [(11)C]erlotinib, for which biliary excretion was also significantly reduced in Abcg2((−/−)) mice). Our data provide evidence for redundancy between P-gp and BCRP in controlling both the brain distribution and biliary excretion of dual P-gp/BCRP substrates and highlight the utility of PET as an upcoming tool to assess the effect of transporters on drug disposition at a whole-body level.