Document Detail


Positron emission tomography studies using (15R)-16-m-[11C]tolyl-17,18,19,20-tetranorisocarbacyclin methyl ester for the evaluation of hepatobiliary transport.
MedLine Citation:
PMID:  20716623     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
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.
Authors:
Tadayuki Takashima; Hiroko Nagata; Takahiro Nakae; Yilong Cui; Yasuhiro Wada; Satoshi Kitamura; Hisashi Doi; Masaaki Suzuki; Kazuya Maeda; Hiroyuki Kusuhara; Yuichi Sugiyama; Yasuyoshi Watanabe
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Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't     Date:  2010-08-17
Journal Detail:
Title:  The Journal of pharmacology and experimental therapeutics     Volume:  335     ISSN:  1521-0103     ISO Abbreviation:  J. Pharmacol. Exp. Ther.     Publication Date:  2010 Nov 
Date Detail:
Created Date:  2010-10-20     Completed Date:  2010-11-23     Revised Date:  -    
Medline Journal Info:
Nlm Unique ID:  0376362     Medline TA:  J Pharmacol Exp Ther     Country:  United States    
Other Details:
Languages:  eng     Pagination:  314-23     Citation Subset:  IM    
Affiliation:
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.
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MeSH Terms
Descriptor/Qualifier:
ATP-Binding Cassette Transporters / genetics
Animals
Bicyclo Compounds / chemistry,  diagnostic use,  pharmacokinetics*
Biliary Tract / metabolism,  radionuclide imaging*
Biological Transport
Carbon Radioisotopes
Chromatography, Thin Layer
Contrast Media / chemistry,  diagnostic use,  pharmacokinetics*
Epoprostenol / analogs & derivatives*,  chemistry,  diagnostic use,  pharmacokinetics
Hyperbilirubinemia / genetics,  metabolism,  radionuclide imaging*
Liver / metabolism,  radionuclide imaging*
Male
Methyl Ethers
Pentanoic Acids / chemistry,  diagnostic use,  pharmacokinetics*
Positron-Emission Tomography / methods*
Rats
Rats, Mutant Strains
Rats, Sprague-Dawley
Tandem Mass Spectrometry
Tissue Distribution
Chemical
Reg. No./Substance:
0/16-m-tolyl-17,18-,19-,20-tetranorisocarbacyclin methyl ester; 0/16-tolyl-17,18,19,20-tetranorisocarbacyclin; 0/ATP-Binding Cassette Transporters; 0/Abcc2 protein, rat; 0/Bicyclo Compounds; 0/Carbon Radioisotopes; 0/Contrast Media; 0/Methyl Ethers; 0/Pentanoic Acids; 35121-78-9/Epoprostenol

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine


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