title: PET imaging-based evaluation of hepatobiliary transport in humans with (15R)-11C-TIC-Me.
abstract: It is well accepted that drug transporters play a pivotal role in hepatobiliary excretion of anionic drugs, in which drug-drug interactions and genetic polymorphisms are known to cause variations. However, PET probes for in vivo functional characterization of these transporters have not been established yet. We used PET to investigate hepatic uptake and subsequent canalicular efflux of (11)C-labeled (15R)-16-m-tolyl-17,18,19,20-tetranorisocarbacyclin methyl ester [(15R)-(11)C-TIC-Me)] in healthy subjects.
  
  
  METHODS
  Serial PET scans of the abdominal region in healthy male subjects were obtained with or without the organic anion-transporting polypeptide (OATP) inhibitor rifampicin after intravenous injection of (15R)-(11)C-TIC-Me as a radiotracer. Venous blood samples and PET images were obtained at frequent intervals up to 30 min after administration of the PET tracer. Dynamic imaging data were evaluated by integration plots of data collected for 2-10 min and for 10-30 min after tracer administration for the determination of tissue uptake clearance and biliary efflux clearance, respectively.
  
  
  RESULTS
  After rapid hydrolysis in blood, the acid form-(11)C-labeled (15R)-16-m-tolyl-17,18,19,20-tetranorisocarbacyclin [(15R)-(11)C-TIC]-accumulated in the liver (37% of the dose by 17 min), and the radioactivity was then excreted into the bile (6.2% by 30 min). Rifampicin (600 mg by mouth), a potent OATP inhibitor, significantly reduced the radioactivity excreted into the bile (by 44%) by inhibiting both uptake (by 45%) and subsequent canalicular efflux (by 62%). (15R)-(11)C-TIC is an in vitro substrate of OATP1B1 and OATP1B3, and clinically relevant concentrations of rifampicin inhibited uptake by OATP1B1 and OATP1B3. These results demonstrated that in humans, (15R)-(11)C-TIC-associated radioactivity is excreted into the bile by organic anion transport systems.
  
  
  CONCLUSIONS
  We demonstrated that PET image analysis with (15R)-(11)C-TIC-Me is useful for investigating variations in OATP function in the human hepatobiliary transport system.
authors.affiliation: RIKEN Center for Molecular Imaging Science, Chuo-ku, Kobe, Hyogo, Japan. ttakashima@riken.jp
authors.forename: Tadayuki
authors.initials: T
authors.lastname: Takashima
authors.forename: Satoshi
authors.initials: S
authors.lastname: Kitamura
authors.forename: Yasuhiro
authors.initials: Y
authors.lastname: Wada
authors.forename: Masaaki
authors.initials: M
authors.lastname: Tanaka
authors.forename: Yoshihito
authors.initials: Y
authors.lastname: Shigihara
authors.forename: Hideki
authors.initials: H
authors.lastname: Ishii
authors.forename: Ryosuke
authors.initials: R
authors.lastname: Ijuin
authors.forename: Susumu
authors.initials: S
authors.lastname: Shiomi
authors.forename: Takahiro
authors.initials: T
authors.lastname: Nakae
authors.forename: Yumiko
authors.initials: Y
authors.lastname: Watanabe
authors.forename: Yilong
authors.initials: Y
authors.lastname: Cui
authors.forename: Hisashi
authors.initials: H
authors.lastname: Doi
authors.forename: Masaaki
authors.initials: M
authors.lastname: Suzuki
authors.forename: Kazuya
authors.initials: K
authors.lastname: Maeda
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: D000005:Abdomen; D000328:Adult; D001648:Bile Canaliculi / Q000187:drug effects / Q000378:metabolism; D001659:Biliary Tract / Q000187:drug effects / Q000378:metabolism*; D001692:Biological Transport / Q000187:drug effects; D001643:Bridged Bicyclo Compounds / Q000097:blood / Q000493:pharmacokinetics*; D002478:Cells, Cultured; D005786:Gene Expression Regulation; D022781:Hepatocytes / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D008099:Liver / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D008297:Male; D008657:Metabolic Clearance Rate / Q000187:drug effects; D027361:Organic Anion Transporters / Q000378:metabolism; D010421:Pentanoic Acids / Q000097:blood / Q000493:pharmacokinetics*; D049268:Positron-Emission Tomography; D012293:Rifampin / Q000494:pharmacology; D013997:Time Factors
chemical_list: C553485:16-m-tolyl-17,18-,19-,20-tetranorisocarbacyclin methyl ester; D001643:Bridged Bicyclo Compounds; D027361:Organic Anion Transporters; D010421:Pentanoic Acids; D012293:Rifampin