Document Detail


Design and characterization of a novel fluorinated magnetic resonance imaging agent for functional analysis of bile Acid transporter activity.
MedLine Citation:
PMID:  23319170     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
PURPOSE: To synthesize a trifluorinated bile acid that can be used for (19)F magnetic resonance imaging (MRI) of bile acid enterohepatic circulation, characterize its in vitro transporter affinity, stability, and (19)F-MRI signal, and assess its ability to concentrate in the gallbladder of C57BL/6 mice.
METHODS: Target compound CA-lys-TFA was synthesized and tested for affinity toward the apical sodium dependent bile acid transporter (hASBT) and the Na+/taurocholate cotransporting polypeptide (hNTCP). In a pilot study, fasted mice were gavaged with vehicle control, 150 mg/kg or 300 mg/kg CA-lys-TFA. CA-lys-TFA in gallbladder, liver and plasma at t = 5 h was quantified. Additionally, a 24-h time course (24 mice across eight time points) was studied using 50 mg/kg CA-lys-TFA.
RESULTS: CA-lys-TFA was a potent substrate of hASBT (Kt = 39.4 μM, normalized Vmax = 0.853) and hNTCP (Kt = 8.99 μM, normalized Vmax = 0.281). (19)F MRI phantom imaging showed linear signal-concentration dependence. In vivo studies showed that rapid accumulation of CA-lys-TFA in the gallbladder was maximal within 4-7 h.
CONCLUSIONS: These findings suggest that CA-lys-TFA, a fluorinated non-radioactive bile acid analogue, has potential for use in MRI to measure in vivo bile acid transport and diagnose bile acid malabsorption and other conditions associated with impaired bile acid transport.
Authors:
Diana Vivian; Kunrong Cheng; Sandeep Khurana; Su Xu; Valerie Whiterock; Drew Witter; Kimberley A Lentz; Kenneth S Santone; Jean-Pierre Raufman; James E Polli
Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural     Date:  2013-01-15
Journal Detail:
Title:  Pharmaceutical research     Volume:  30     ISSN:  1573-904X     ISO Abbreviation:  Pharm. Res.     Publication Date:  2013 May 
Date Detail:
Created Date:  2013-04-05     Completed Date:  2013-09-18     Revised Date:  2014-05-07    
Medline Journal Info:
Nlm Unique ID:  8406521     Medline TA:  Pharm Res     Country:  United States    
Other Details:
Languages:  eng     Pagination:  1240-51     Citation Subset:  IM    
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MeSH Terms
Descriptor/Qualifier:
Animals
Bile Acids and Salts / analysis*,  chemical synthesis,  metabolism*
Cell Line
Gallbladder / metabolism*
Halogenation
Humans
Liver / ultrastructure
Magnetic Resonance Imaging*
Mice
Mice, Inbred C57BL
Organic Anion Transporters, Sodium-Dependent / metabolism*
Stomach / ultrastructure
Symporters / metabolism*
Grant Support
ID/Acronym/Agency:
DK67530/DK/NIDDK NIH HHS; K08DKO81479//PHS HHS; R01 DK067530/DK/NIDDK NIH HHS; R21 DK093406/DK/NIDDK NIH HHS; R21 DK093406/DK/NIDDK NIH HHS; T32 DK067872/DK/NIDDK NIH HHS; T32 DK067872/DK/NIDDK NIH HHS
Chemical
Reg. No./Substance:
0/Bile Acids and Salts; 0/Organic Anion Transporters, Sodium-Dependent; 0/Symporters; 145420-23-1/sodium-bile acid cotransporter
Comments/Corrections

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