title: Evaluation of breast cancer resistance protein function in hepatobiliary and renal excretion using PET with 11C-SC-62807.
abstract: A quantitative PET imaging method was used to assess the in vivo kinetics of hepatobiliary and renal excretion of the breast cancer resistance protein (Bcrp) substrate (11)C-SC-62807 in mice.
  
  
  METHODS
  Serial abdominal PET scans were collected in wild-type and Bcrp knockout (Bcrp(-/-)) mice after intravenous injection of (11)C-SC-62807. Venous blood samples and PET images were obtained at frequent intervals up to 30 min after radiotracer administration. Dynamic PET data were analyzed to determine the canalicular and brush-border efflux clearances in the liver and kidney (CL(int,bile,liver) and CL(int,urine,kidney), respectively).
  
  
  RESULTS
  SC-62807 is an in vitro substrate of mouse Bcrp and human BCRP. Radioactivity associated with (11)C-SC-62807 was predominantly found in the blood, liver, bile, and urine 30 min after administration. Both biliary and urinary excretion of radioactivity was markedly lower in Bcrp(-/-) mice than in wild-type mice, suggesting greater systemic exposure in Bcrp(-/-) mice. Both the CL(int,bile,liver) and the CL(int,urine,kidney) were significantly lower in Bcrp(-/-) mice (74% ± 10% and 99% ± 1% lower than controls, respectively). We also found that (11)C-SC-62807 is a substrate of the organic anion-transporting polypeptides OATP1B1 and OATP1B3 in vitro.
  
  
  CONCLUSIONS
  The present study demonstrated that Bcrp plays a significant role in the efflux of (11)C-SC-62807 in mouse liver and kidney. We also demonstrated the feasibility of PET using (11)C-SC-62807 to study the activity of BCRP in humans.
authors.affiliation: Molecular Probe Dynamics Laboratory, RIKEN Center for Molecular Imaging Science, Kobe, Japan. ttakashima@riken.jp
authors.forename: Tadayuki
authors.initials: T
authors.lastname: Takashima
authors.forename: Chunyong
authors.initials: C
authors.lastname: Wu
authors.forename: Misato
authors.initials: M
authors.lastname: Takashima-Hirano
authors.forename: Yumiko
authors.initials: Y
authors.lastname: Katayama
authors.forename: Yasuhiro
authors.initials: Y
authors.lastname: Wada
authors.forename: Masaaki
authors.initials: M
authors.lastname: Suzuki
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Kusuhara
authors.forename: Yuichi
authors.initials: Y
authors.lastname: Sugiyama
authors.forename: Yasuyoshi
authors.initials: Y
authors.lastname: Watanabe
mesh_terms: D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2; D018528:ATP-Binding Cassette Transporters / Q000378:metabolism*; D000818:Animals; D019540:Area Under Curve; D001659:Biliary Tract / Q000378:metabolism*; D002250:Carbon Radioisotopes / Q000494:pharmacology*; D002851:Chromatography, High Pressure Liquid / Q000379:methods; D004305:Dose-Response Relationship, Drug; D005786:Gene Expression Regulation; D057809:HEK293 Cells; D006801:Humans; D007668:Kidney / Q000378:metabolism*; D007700:Kinetics; D008099:Liver / Q000378:metabolism*; D008297:Male; D051379:Mice; D008956:Models, Chemical; D009363:Neoplasm Proteins / Q000378:metabolism*; D049268:Positron-Emission Tomography / Q000379:methods*; D011720:Pyrazoles / Q000494:pharmacology*; D013449:Sulfonamides / Q000494:pharmacology*; D013997:Time Factors
chemical_list: C116614:ABCG2 protein, human; D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2; D018528:ATP-Binding Cassette Transporters; C501412:Abcg2 protein, mouse; D002250:Carbon Radioisotopes; D009363:Neoplasm Proteins; D011720:Pyrazoles; C560337:SC-62807; D013449:Sulfonamides