Positron emission tomography studies using (15R)-16-m-[11C]tolyl-17,18,19,20-tetranorisocarbacyclin methyl ester for the evaluation of hepatobiliary transport.
A quantitative positron emission tomography (PET) methodology was developed for in vivo kinetic analysis of hepatobiliary transport. Serial abdominal PET scans were performed on normal and multidrug resistance-associated protein 2 (Mrp2)-deficient rats after intravenous injection of (15R)-16-m-[(11)C]tolyl-17,18,19,20-tetranorisocarbacyclin methyl ester (15R-[(11)C] TIC-Me) as a radiotracer. 15R-[(11)C]TIC-Me was rapidly converted to its acid form in blood within 10 s. PET scans revealed that 15R-[(11)C]TIC was localized mainly in the liver within 5 min of injection. By 90 min, total radioactivity in bile of Mrp2-deficient rats was significantly reduced compared with controls. Metabolite analysis by thin-layer chromatography autoradiography showed that 15R-[(11)C]TIC is converted to at least three metabolites (M1, M2, and M3), and M2 and M3 are the major metabolites in plasma and bile, respectively. Hepatic uptake clearance of total radioactivity in normal rats was close to the hepatic blood flow rate and slightly higher than that in Mrp2-deficient rats. The intrinsic canalicular efflux clearance of M3 (CL(int,bile,M3)) in Mrp2-deficient rats was decreased to 12% of controls, whereas clearance of M2 was moderately decreased (54%). An in vitro transport assay detected ATP-dependent uptake of both M2 and M3 by rat Mrp2-expressing membrane vesicles. These results demonstrated that M3 is excreted primarily into the bile by Mrp2 in normal rats. We conclude that PET studies using 15R-[(11)C]TIC-Me could be useful for in vivo analyses of Mrp2-mediated hepatobiliary transport.
Takashima
Tadayuki
T
Molecular Probe Dynamics Laboratory, RIKEN Center for Molecular Imaging Science, 6-7-3 Minatojima-minamimachi, Chuo-ku, Kobe, Hyogo 650-0047, Japan. ttakashima@riken.jp.
Nagata
Hiroko
H
Nakae
Takahiro
T
Cui
Yilong
Y
Wada
Yasuhiro
Y
Kitamura
Satoshi
S
Doi
Hisashi
H
Suzuki
Masaaki
M
Maeda
Kazuya
K
Kusuhara
Hiroyuki
H
Sugiyama
Yuichi
Y
Watanabe
Yasuyoshi
Y
D018528:ATP-Binding Cassette Transporters / Q000235:genetics; D000818:Animals; D001659:Biliary Tract / Q000000981:diagnostic imaging* / Q000378:metabolism; D001692:Biological Transport; D001643:Bridged Bicyclo Compounds / Q000737:chemistry / Q000493:pharmacokinetics*; D002250:Carbon Radioisotopes; D002855:Chromatography, Thin Layer; D003287:Contrast Media / Q000737:chemistry / Q000493:pharmacokinetics*; D011464:Epoprostenol / Q000031:analogs & derivatives* / Q000737:chemistry / Q000493:pharmacokinetics; D006932:Hyperbilirubinemia / Q000000981:diagnostic imaging* / Q000235:genetics / Q000378:metabolism; D008099:Liver / Q000000981:diagnostic imaging* / Q000378:metabolism; D008297:Male; D008738:Methyl Ethers; D010421:Pentanoic Acids / Q000737:chemistry / Q000493:pharmacokinetics*; D049268:Positron-Emission Tomography / Q000379:methods*; D051381:Rats; D011922:Rats, Mutant Strains; D017207:Rats, Sprague-Dawley; D053719:Tandem Mass Spectrometry; D014018:Tissue Distribution
C553485:16-m-tolyl-17,18-,19-,20-tetranorisocarbacyclin methyl ester; C119304:16-tolyl-17,18,19,20-tetranorisocarbacyclin; D018528:ATP-Binding Cassette Transporters; C423013:Abcc2 protein, rat; D001643:Bridged Bicyclo Compounds; D002250:Carbon Radioisotopes; D003287:Contrast Media; D008738:Methyl Ethers; D010421:Pentanoic Acids; D011464:Epoprostenol