Evaluation of Breast Cancer Resistance Protein Function in Hepatobiliary and Renal Excretion Using PET

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 (CLint,bile,liver and CLint,urine,kidney ,r espectively). Results: SC-62807 is an in vitro substrate of mouse Bcrp and human BCRP. Radioactivity associated with 11C-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 CLint,bile,liver and the CLint,urine,kidney were significantly lower in Bcrp –/– mice (74% 6 10% and 99% 6 1% lower than controls, respectively). We also found that 11 C-SC62807 is a substrate of the organic anion-transporting polypeptides OATP1B1 and OATP1B3 in vitro. Conclusion: 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