In Vivo Magnetic Resonance Imaging to Detect Biliary Excretion of <sup>19</sup>F-Labeled Drug in Mice

Raufman, Jean Pierre; Xu, Su; Cheng, Kunrong; Khurana, Sandeep; Johnson, Diana; Shao, Changxing; Kane, Maureen A.; Shi, Da; Gullapalli, Rao P.; Polli, James E.

doi:10.1124/dmd.110.037358

Cited by 6 publications

(13 citation statements)

References 16 publications

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“…Using this method, there is greater than 99% confidence that voxels containing bile acid analogue concentrations above 6.82 mM relative to the phantom are from actual 19 F signal, and not noise. This limit of detection was similar to that estimated for isoflurane [ 26 ]. We used liquid chromatography–mass spectrometry (LC–MS) to measure isoflurane in the gallbladder.…”

Section: Development Of 19 F-labeled Bile Acid Anasupporting

confidence: 86%

A 19F magnetic resonance imaging-based diagnostic test for bile acid diarrhea

Raufman

Metry

Felton

et al. 2018

Magn Reson Mater Phy

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In up to 50% of people diagnosed with a common ailment, diarrhea-predominant irritable bowel syndrome, diarrhea results from excess spillage of bile acids into the colon—data emerging over the past decade identified deficient release of a gut hormone, fibroblast growth factor 19 (FGF19), and a consequent lack of feedback suppression of bile acid synthesis as the most common cause. 75 Selenium homotaurocholic acid (SeHCAT) testing, considered the most sensitive and specific means of identifying individuals with bile acid diarrhea, is unavailable in many countries, including the United States. Other than SeHCAT, tests to diagnose bile acid diarrhea are cumbersome, non-specific, or insufficiently validated; clinicians commonly rely on a therapeutic trial of bile acid binders. Here, we review bile acid synthesis and transport, the pathogenesis of bile acid diarrhea, the reasons clinicians frequently overlook this disorder, including the limitations of currently available tests, and our efforts to develop a novel 19 F magnetic resonance imaging (MRI)-based diagnostic approach. We created 19 F-labeled bile acid analogues whose in vitro and in vivo transport mimics that of naturally occurring bile acids. Using dual 1 H/ 19 F MRI of the gallbladders of live mice fed 19 F-labeled bile acid analogues, we were able to differentiate wild-type mice from strains deficient in intestinal expression of a key bile acid transporter, the apical sodium-dependent bile acid transporter (ASBT), or FGF15, the mouse homologue of FGF19. In addition to reviewing our development of 19 F-labeled bile acid analogue-MRI to diagnose bile acid diarrhea, we discuss challenges to its clinical implementation. A major limitation is the paucity of clinical MRI facilities equipped with the appropriate coil and software needed to detect 19 F signals.

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Section: Development Of 19 F-labeled Bile Acid Anasupporting

confidence: 86%

A 19F magnetic resonance imaging-based diagnostic test for bile acid diarrhea

Raufman

Metry

Felton

et al. 2018

Magn Reson Mater Phy

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“…Its octanol/water partition coefficient is 3.7 compared with chenodeoxycholic acid's partition coefficient of 23.3 (38). 19 F-MRI requires the imaging agent to be in solution, and we already calculated the limit of detection of a trifluorinated compound to be approximately 1 mM (13). Additionally, higher aqueous solubility reduces the passive permeability of the compound, allowing for a more specific analysis of active transporter function in enterohepatic circulation.…”

Section: Discussionmentioning

confidence: 99%

“…We determined the limit of detection of isoflurane by 19 F MRI imaging to be approximately 1 mM, equivalent to 3 mM total fluorine atoms (13). In the present report, our objectives were to synthesize a trifluorinated bile acid; characterize in vitro its affinity for bile acid transporters,stability and 19 F MRI signal; and measure its ability to concentrate in the murine gallbladder above the 19 F MRI limit of detection.…”

Section: Introductionmentioning

confidence: 99%

Design and Characterization of a Novel Fluorinated Magnetic Resonance Imaging Agent for Functional Analysis of Bile Acid Transporter Activity

et al. 2013

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Purpose Our objectives were to synthesize a trifluorinated bile acid that can be used for 19F magnetic resonance imaging (MRI) of bile acid enterohepatic circulation, characterize its in vitro transporter affinity, stability, and 19F-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). 19F 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. Conclusion 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.

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“…20 In the present work CA-lys-TFA, a novel bile acid analogue, was successfully and reproducibly imaged in the murine gallbladder using 19 F MRI. To our knowledge, this represents the first report that a drug absorbed orally can be imaged in vivo by 19 F MRI.…”

Section: Discussionmentioning

confidence: 90%

In Vivo Performance of a Novel Fluorinated Magnetic Resonance Imaging Agent for Functional Analysis of Bile Acid Transport

Vivian

Cheng²,

Khurana³

et al. 2014

Mol. Pharmaceutics

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A novel trifluorinated cholic acid derivative, CA-lys-TFA, was designed and synthesized for use as a tool to measure bile acid transport noninvasively using magnetic resonance imaging (MRI). In the present study, the in vivo performance of CA-lys-TFA for measuring bile acid transport by MRI was investigated in mice. Gallbladder CA-lys-TFA content was quantified using MRI and liquid chromatography/tandem mass spectrometry. Results in wild-type (WT) C57BL/6J mice were compared to those in mice lacking expression of Asbt, the ileal bile acid transporter. 19F signals emanating from the gallbladders of WT mice 7 h after oral gavage with 150 mg/kg CA-lys-TFA were reproducibly detected by MRI. Asbt-deficient mice administered the same dose had undetectable 19F signals by MRI, and gallbladder bile CA-lys-TFA levels were 30-fold lower compared to WT animals. To our knowledge, this represents the first report of in vivo imaging of an orally absorbed drug using 19F MRI. Fluorinated bile acid analogues have potential as tools to measure and detect abnormal bile acid transport by MRI.

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In Vivo Magnetic Resonance Imaging to Detect Biliary Excretion of ¹⁹F-Labeled Drug in Mice

Cited by 6 publications

References 16 publications

A 19F magnetic resonance imaging-based diagnostic test for bile acid diarrhea

A 19F magnetic resonance imaging-based diagnostic test for bile acid diarrhea

Design and Characterization of a Novel Fluorinated Magnetic Resonance Imaging Agent for Functional Analysis of Bile Acid Transporter Activity

In Vivo Performance of a Novel Fluorinated Magnetic Resonance Imaging Agent for Functional Analysis of Bile Acid Transport

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In Vivo Magnetic Resonance Imaging to Detect Biliary Excretion of 19F-Labeled Drug in Mice

Cited by 6 publications

References 16 publications

A 19F magnetic resonance imaging-based diagnostic test for bile acid diarrhea

A 19F magnetic resonance imaging-based diagnostic test for bile acid diarrhea

Design and Characterization of a Novel Fluorinated Magnetic Resonance Imaging Agent for Functional Analysis of Bile Acid Transporter Activity

In Vivo Performance of a Novel Fluorinated Magnetic Resonance Imaging Agent for Functional Analysis of Bile Acid Transport

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In Vivo Magnetic Resonance Imaging to Detect Biliary Excretion of ¹⁹F-Labeled Drug in Mice