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J Pharm Sci. 2014 Nov;103(11):3782-3792. doi: 10.1002/jps.24131. Epub 2014 Sep 5.

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

Author information

1
Department of Pharmaceutical Sciences, University of Maryland School of Pharmacy, Baltimore, Maryland 21230.
2
Department of Medicine, University of Maryland School of Medicine, Baltimore, Maryland 21230.
3
Department of Diagnostic Radiology and Nuclear Medicine, University of Maryland School of Medicine, Baltimore, Maryland 21230.
4
Division of Pediatric Gastroenterology, Hepatology, and Nutrition, Emory University School of Medicine, Atlanta, Georgia 30322.
5
Department of Medicine, University of Maryland School of Medicine, Baltimore, Maryland 21230. Electronic address: jraufman@medicine.umaryland.edu.
6
Department of Pharmaceutical Sciences, University of Maryland School of Pharmacy, Baltimore, Maryland 21230. Electronic address: jpolli@rx.umaryland.edu.

Abstract

Previously, we developed a trifluorinated bile acid, CA-lys-TFA, with the objective of noninvasively assessing bile acid transport in vivo using (19) F 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.

KEYWORDS:

bile acid malabsorption; bile acid transporters; biliary excretion; enterohepatic circulation; fluorine MRI; imaging methods; intestinal absorption; site-specific delivery; targeted drug delivery; transporters

PMID:
25196788
PMCID:
PMC4206604
DOI:
10.1002/jps.24131
[Indexed for MEDLINE]
Free PMC Article

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