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Attenuated Accumulation of Novel Fluorine (19F)-Labeled Bile Acid Analogues in Gallbladders of Fibroblast Growth Factor-15 (FGF15)-Deficient Mice
Molecular Pharmaceutics ( IF 4.9 ) Pub Date : 2018-09-24 00:00:00 , DOI: 10.1021/acs.molpharmaceut.8b00454
Melissa Metry 1 , Jessica Felton 2 , Kunrong Cheng 3 , Su Xu 4 , Yong Ai 1 , Fengtian Xue 1 , Jean-Pierre Raufman 3 , James E. Polli 1
Affiliation  

Our work has focused on defining the utility of fluorine (19F)-labeled bile acid analogues and magnetic resonance imaging (MRI) to identify altered bile acid transport in vivo. In the current study, we explored the ability of this approach to differentiate fibroblast growth factor-15 (FGF15)-deficient from wild-type (WT) mice, a potential diagnostic test for bile acid diarrhea, a commonly misdiagnosed disorder. FGF15 is the murine homologue of human FGF19, an intestinal hormone whose deficiency is an underappreciated cause of bile acid diarrhea. In a pilot and three subsequent pharmacokinetic studies, we treated mice with two 19F-labeled bile acid analogues, CA-lys-TFA and CA-sar-TFMA. After oral dosing, we quantified 19F-labeled bile acid analogue levels in the gallbladder, liver, small and large intestine, and plasma using liquid chromatography mass spectrometry (LC–MS/MS). Both 19F bile acid analogues concentrated in the gallbladders of FGF15-deficient and WT mice, attaining peak concentrations at approximately 8.5 h after oral dosing. However, analogue levels in gallbladders of FGF15-deficient mice were several-fold less compared to those in WT mice. Live-animal 19F MRI provided agreement with our LC–MS/MS-based measures; we detected robust CA-lys-TFA 19F signals in gallbladders of WT mice but no signals in FGF15-deficient mice. Our finding that 19F MRI differentiates FGF15-deficient from WT mice provides additional proof-of-concept for the development of 19F bile acid analogues and 19F MRI as a clinical test to diagnose bile acid diarrhea due to FGF19 deficiency and other disorders.

中文翻译:

在成纤维细胞生长因子15(FGF15)缺陷的小鼠胆囊中新型氟(19 F)标记胆汁酸类似物的衰减的积累。

我们的工作集中于定义氟(19 F)标记的胆汁酸类似物和磁共振成像(MRI)的效用,以识别体内改变的胆汁酸转运。在当前的研究中,我们探索了这种方法从野生型(WT)小鼠中区分成纤维细胞生长因子15(FGF15)缺陷的能力,这是胆汁酸腹泻(一种通常被误诊的疾病)的潜在诊断测试。FGF15是人FGF19(一种肠道激素,其缺乏是胆汁酸腹泻的一种未被充分认识的原因)的鼠源同源物。在一项先导研究和随后的三项药代动力学研究中,我们用两种19 F标记的胆汁酸类似物CA-lys-TFA和CA-sar-TFMA处理了小鼠。口服给药后,我们量化了19使用液相色谱质谱法(LC-MS / MS)在胆囊,肝,小肠和大肠以及血浆中用F标记的胆汁酸类似物水平。两种19 F胆汁酸类似物均浓缩在FGF15缺陷型和WT小鼠的胆囊中,口服后约8.5 h达到峰值浓度。但是,与WT小鼠相比,缺乏FGF15的小鼠胆囊中的类似物水平要低几倍。活体19 F MRI证实了我们基于LC-MS / MS的测量方法;我们在野生型小鼠胆囊中检测到了强有力的CA-lys-TFA 19 F信号,而在FGF15缺陷型小鼠中未检测到信号。我们发现19F MRI将WT15缺陷型小鼠与WT小鼠区分开来,为19 F胆汁酸类似物的发展提供了另外的概念证明,而19 F MRI作为诊断由FGF19缺陷和其他疾病引起的胆汁酸腹泻的临床试验。
更新日期:2018-09-24
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