title: 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 (99m)Tc-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 (99m)Tc-mebrofenin (n = 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 (99m)Tc-mebrofenin 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 (99m)Tc-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. (99m)Tc-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).
  
  
  CONCLUSIONS
  The current study visualized and quantified hepatic uptake and biliary efflux of (99m)Tc-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.
authors: Laboratory of Radiopharmacy, Ghent University, Ghent, Belgium. sara.neyt@ugent.be
authors: Sara
authors: S
authors: Neyt
authors: Maarten T
authors: MT
authors: Huisman
authors: Christian
authors: C
authors: Vanhove
authors: Hilde
authors: H
authors: De Man
authors: Maarten
authors: M
authors: Vliegen
authors: Lieselotte
authors: L
authors: Moerman
authors: Caroline
authors: C
authors: Dumolyn
authors: Geert
authors: G
authors: Mannens
authors: Filip
authors: F
authors: De Vos
mesh_terms: D018435:ATP Binding Cassette Transporter, Subfamily B / Q000378:metabolism*; D000814:Aniline Compounds; D000818:Animals; D001652:Bile Ducts / Q000187:drug effects / Q000378:metabolism* / Q000601:surgery; D001692:Biological Transport / Q000187:drug effects; D016466:CHO Cells; D006224:Cricetinae; D003412:Cricetulus; D004305:Dose-Response Relationship, Drug; D005260:Female; D005998:Glycine; D007098:Imino Acids / Q000378:metabolism*; D008026:Ligation; D008099:Liver / Q000000981:diagnostic imaging / Q000187:drug effects / Q000378:metabolism*; D051379:Mice; D027362:Organic Anion Transport Protein 1 / Q000378:metabolism*; D029362:Organic Anion Transporters, Sodium-Independent / Q000378:metabolism*; D027702:Organic Cation Transporter 1 / Q000378:metabolism; D015609:Organotechnetium Compounds / Q000378:metabolism*; D012293:Rifampin / Q000494:pharmacology; D015899:Tomography, Emission-Computed, Single-Photon; D000097202:ATP-Binding Cassette Sub-Family B Member 4
chemical_list: D018435:ATP Binding Cassette Transporter, Subfamily B; D000814:Aniline Compounds; D005998:Glycine; D007098:Imino Acids; D027362:Organic Anion Transport Protein 1; D029362:Organic Anion Transporters, Sodium-Independent; D027702:Organic Cation Transporter 1; D015609:Organotechnetium Compounds; D012293:Rifampin; D000097202:ATP-Binding Cassette Sub-Family B Member 4; C490281:Slc22a7 protein, mouse; C034837:technetium Tc 99m mebrofenin