Abstract
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 [11C]tariquidar, [11C]erlotinib, and [11C]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 [11C]tariquidar, [11C]erlotinib, or [11C]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 [11C]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.
Highlights
The adenosine triphosphate-binding cassette (ABC) transporters P-glycoprotein (P-gp, encoded in humans by the ABCB1 gene and in rodents by the Abcb1a and Abcb1b genes, and breast cancer resistance protein (BCRP, encoded in humans by the ABCG2 gene and in rodents by the Abcg2 gene) are two important efflux transporters that are widely expressed throughout the body [1]
We evaluated whether the known functional redundancy between
P-gp and BCRP at the BBB extends to the canalicular membrane of hepatocytes, where both transporters mediate the biliary excretion of drugs and their metabolites
Summary
The adenosine triphosphate-binding cassette (ABC) transporters P-glycoprotein (P-gp, encoded in humans by the ABCB1 gene and in rodents by the Abcb1a and Abcb1b genes, and breast cancer resistance protein (BCRP, encoded in humans by the ABCG2 gene and in rodents by the Abcg gene) are two important efflux transporters that are widely expressed throughout the body [1]. These two membrane transporters have a broad and largely overlapping substrate spectrum, including a variety of clinically used drugs, such as most molecularly targeted anticancer drugs [2,3]. P-gp and BCRP may become overexpressed in certain tumors, in which they can contribute to multidrug resistance by limiting cellular entry of anticancer drugs [8]
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