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 [C]tariquidar, [C]erlotinib, and [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, , , and mice underwent dynamic whole-body PET scans after i.v. injection of either [C]tariquidar, [C]erlotinib, or [C]elacridar. Brain uptake of all three radiotracers was markedly higher in mice than in wild-type mice, while only moderately changed in and mice. The transfer of radioactivity from liver to excreted bile was significantly lower in mice and almost unchanged in and mice (with the exception of [C]erlotinib, for which biliary excretion was also significantly reduced in 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.