Design and evaluation of a novel trifluorinated imaging agent for assessment of bile acid transport using fluorine magnetic resonance imaging

Diana Vivian, Kunrong Cheng, Sandeep Khurana, Su Xu, Paul A. Dawson, Jean Pierre Raufman, James E. Polli

Research output: Contribution to journalArticle

9 Scopus citations

Abstract

Previously, we developed a trifluorinated bile acid, CA-lys-TFA, with the objective of noninvasively assessing bile acid transport in vivo using 19F magnetic resonance imaging (MRI). CA-lys-TFA was successfully imaged in the mouse gallbladder, but was susceptible to deconjugation in vitro by choloylglycine hydrolase (CGH), a bacterial bile acid deconjugating enzyme found in the terminal ileum and colon. The objective of the present study was to develop a novel trifluorinated bile acid resistant to deconjugation by CGH. CA-sar-TFMA was designed, synthesized, and tested for in vitro transport properties, stability, imaging properties, and its ability to differentially accumulate in the gallbladders of normal mice, compared with mice with known impaired bile acid transport (deficient in the apical sodium-dependent bile acid transporter, ASBT). CA-sar-TFMA was a potent inhibitor and substrate of ASBT and the Na+/taurocholate cotransporting polypeptide. Stability was favorable in all conditions tested, including the presence of CGH. CA-sar-TFMA was successfully imaged and accumulated at 16.1-fold higher concentrations in gallbladders from wild-type mice compared with those from Asbt-deficient mice. Our results support the potential of using MRI with CA-sar-TFMA as a noninvasive method to assess bile acid transport in vivo.

Original languageEnglish (US)
Pages (from-to)3782-3792
Number of pages11
JournalJournal of Pharmaceutical Sciences
Volume103
Issue number11
DOIs
StatePublished - Nov 2014

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Keywords

  • Bile acid malabsorption
  • Bile acid transporters
  • Biliary excretion
  • Enterohepatic circulation
  • Fluorine MRI
  • Imaging methods
  • Intestinal absorption
  • Site-specific delivery
  • Targeted drug delivery
  • Transporters

ASJC Scopus subject areas

  • Pharmaceutical Science

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