title: Design and evaluation of a novel trifluorinated imaging agent for assessment of bile acid transport using fluorine magnetic resonance imaging.
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.
authors.affiliation: Department of Pharmaceutical Sciences, University of Maryland School of Pharmacy, Baltimore, Maryland 21230.
authors.forename: Diana
authors.initials: D
authors.lastname: Vivian
authors.affiliation: Department of Medicine, University of Maryland School of Medicine, Baltimore, Maryland 21230.
authors.forename: Kunrong
authors.initials: K
authors.lastname: Cheng
authors.affiliation: Department of Medicine, University of Maryland School of Medicine, Baltimore, Maryland 21230.
authors.forename: Sandeep
authors.initials: S
authors.lastname: Khurana
authors.affiliation: Department of Diagnostic Radiology and Nuclear Medicine, University of Maryland School of Medicine, Baltimore, Maryland 21230.
authors.forename: Su
authors.initials: S
authors.lastname: Xu
authors.affiliation: Division of Pediatric Gastroenterology, Hepatology, and Nutrition, Emory University School of Medicine, Atlanta, Georgia 30322.
authors.forename: Paul A
authors.initials: PA
authors.lastname: Dawson
authors.affiliation: Department of Medicine, University of Maryland School of Medicine, Baltimore, Maryland 21230. Electronic address: jraufman@medicine.umaryland.edu.
authors.forename: Jean-Pierre
authors.initials: JP
authors.lastname: Raufman
authors.affiliation: Department of Pharmaceutical Sciences, University of Maryland School of Pharmacy, Baltimore, Maryland 21230. Electronic address: jpolli@rx.umaryland.edu.
authors.forename: James E
authors.initials: JE
authors.lastname: Polli
mesh_terms: D000284:Administration, Oral; D000818:Animals; D001692:Biological Transport; D019826:Cholic Acid / Q000008:administration & dosage / Q000493:pharmacokinetics; D003287:Contrast Media / Q000008:administration & dosage / Q000493:pharmacokinetics; D004285:Dogs; D066235:Fluorine-19 Magnetic Resonance Imaging / Q000295:instrumentation; D005704:Gallbladder / Q000378:metabolism*; D057809:HEK293 Cells; D006801:Humans; D007413:Intestinal Mucosa / Q000378:metabolism*; D008239:Lysine / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000493:pharmacokinetics; D061985:Madin Darby Canine Kidney Cells; D008297:Male; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D029363:Organic Anion Transporters, Sodium-Dependent / Q000172:deficiency / Q000235:genetics; D019047:Phantoms, Imaging; D010865:Pilot Projects; D027981:Symporters / Q000172:deficiency / Q000235:genetics; D014018:Tissue Distribution; D014162:Transfection
chemical_list: D003287:Contrast Media; C072409:N-epsilon-trifluoro-lysine; D029363:Organic Anion Transporters, Sodium-Dependent; D027981:Symporters; C071908:sodium-bile acid cotransporter; D019826:Cholic Acid; D008239:Lysine
keywords: bile acid malabsorption; bile acid transporters; biliary excretion; enterohepatic circulation; fluorine MRI; imaging methods; intestinal absorption; site-specific delivery; targeted drug delivery; transporters