In vivo visualization and quantification of (disturbed) Oatp-mediated hepatic uptake and Mrp2-mediated biliary excretion of 99mTc- mebrofenin in mice

Abstract

Hepatic transport of 99mTc-mebrofenin through organic anion transport protein 1a and 1b (Oatp1a/1b) and multidrug resistance protein 2 (Mrp2) was investigated by small-animal SPECT. On the basis of the results, a noninvasive method to visualize and quantify disturbances in hepatic transport is proposed. Methods: Friend virus B wild-type mice (untreated, bile duct- ligated, vehicle- or rifampicin-treated) and strain-matched knockout mice unable to express the uptake transporters Oatp1a/1b (Slco1a/1b-/-/-/-) or the efflux transporter Mrp2 (Abcc2-/-) were intravenously injected with 99mTc-mebrofenin (n 5 3 per group). After dynamic small-animal SPECT and short CT acquisitions, time-activity curves of the liver and of the gallbladder and intestines were obtained and correlated with direct blood samples. Results: Normal hepatobiliary clearance of 99mTcmebrofenin was severely impaired in the bile duct-ligated animal, as evidenced by elevated hepatic tracer levels. In Slco1a/ 1b-/-/-/- mice, a lower area under the curve (AUC) for the liver (P = 0.014) was obtained and no activity was detected in the gallbladder and intestines. Renal rerouting was observed, along with an increase in the blood AUC (P = 0.01). Abcc2-/- mice had a higher liver AUC (P = 0.009), a delayed emergence time of 99mTc- mebrofenin in the gallbladder (P = 0.009), and a lower AUC for the gallbladder and intestines (P = 0.001). The blood curve was similar to that of wild-type mice. 99mTc-mebrofenin disposition was altered after rifampicin treatments. We observed a dose-dependent delayed time point at which tracer maximized in liver, an increased AUC for liver, and a lower AUC for gallbladder and intestines (P = 0.042, 0.034, and 0.001, respectively, highest dose). Emergence in the gallbladder occurred later (P = 0.009, highest dose), and blood AUC was higher (P = 0.006). Conclusion: The current study visualized and quantified hepatic uptake and biliary efflux of 99mTc-mebrofenin. Our results demonstrated the possibility of discriminating, on a quantitative level, between lack of functional activity of sinusoidal uptake versus that of biliary efflux transporters. COPYRIGHT © 2013 by the Society of Nuclear Medicine and Molecular Imaging, Inc.