Lillienau J, Schteingart C D, Hofmann A F
Department of Medicine, University of California, San Diego, La Jolla 92093.
J Clin Invest. 1992 Feb;89(2):420-31. doi: 10.1172/JCI115601.
The properties of cholylsarcosine (the synthetic N-acyl conjugate of cholic acid with sarcosine [N-methylglycine]) were examined to determine its suitability as a bile acid replacement agent for conditions of bile acid deficiency in the small intestine, which causes fat malabsorption. Previous studies in rodents had shown that the compound was well transported by the liver and ileum and underwent neither deconjugation nor dehydroxylation during enterohepatic cycling. By 1H-nuclear magnetic resonance, cholylsarcosine was found to exist in dilute aqueous solution as an almost equimolar mixture of two geometric isomers--cis and trans (around the amide bond)--in contrast to cholylglycine, which was present entirely in the trans form. The critical micellization concentration was 11 mmol/liter, similar to that of cholylglycine (10 mmol/liter). By nonaqueous titrimetry, the pKa' of cholylsarcosine was 3.7, only slightly lower than that of cholylglycine (3.9). Cholylsarcosine was poorly soluble below pH 3.7, but highly soluble above pH 4. In vitro, cholylsarcosine behaved as cholylglycine with respect to promoting lipolysis by lipase/colipase. There was little difference between cholylsarcosine and cholylglycine in their solubilization of an equimolar mixture of oleic acid, oleate, and monoolein (designed to simulate digestive products of triglyceride) or in their solubilization of monooleyl-glycerol alone. When a [3H]triolein emulsion with either cholylsarcosine or cholyltaurine was infused intraduodenally in biliary fistula rats, recovery of 3H in lymph was 52 +/- 10% (mean +/- SD) for cholylsarcosine and 52 +/- 11% for cholyltaurine. When perfused into the colon of the anesthetized rabbit, cholylsarcosine (5 mmol/liter) did not influence water absorption or permeability to erythritol, in contrast to chenodeoxycholate, which induced vigorous water secretion and caused erythritol loss. We conclude that cholylsarcosine possesses the physicochemical and physiological properties required for a suitable bile acid replacement in deficiency states.
对胆酰肌氨酸（胆酸与肌氨酸[N - 甲基甘氨酸]的合成N - 酰基共轭物）的性质进行了研究，以确定其作为胆汁酸替代剂用于小肠胆汁酸缺乏症（可导致脂肪吸收不良）的适用性。先前在啮齿动物中的研究表明，该化合物在肝脏和回肠中转运良好，在肠肝循环过程中既不发生去共轭作用也不发生脱羟基作用。通过1H - 核磁共振发现，胆酰肌氨酸在稀水溶液中以两种几何异构体（顺式和反式，围绕酰胺键）的几乎等摩尔混合物形式存在，这与完全以反式形式存在的胆酰甘氨酸不同。其临界胶束浓度为11 mmol/升，与胆酰甘氨酸的临界胶束浓度（10 mmol/升）相似。通过非水滴定法测定，胆酰肌氨酸的pKa'为3.7，仅略低于胆酰甘氨酸的pKa'（3.9）。胆酰肌氨酸在pH 3.7以下溶解度较差，但在pH 4以上高度可溶。在体外，就促进脂肪酶/辅脂肪酶介导的脂肪分解而言，胆酰肌氨酸的表现与胆酰甘氨酸相似。在溶解油酸、油酸盐和甘油单油酸酯的等摩尔混合物（旨在模拟甘油三酯的消化产物）或单独溶解甘油单油酸酯方面，胆酰肌氨酸和胆酰甘氨酸之间几乎没有差异。当将含有胆酰肌氨酸或胆酰牛磺酸的[3H]三油酸甘油酯乳剂经十二指肠内注入胆管瘘大鼠体内时，胆酰肌氨酸组淋巴中3H的回收率为52±10%（平均值±标准差），胆酰牛磺酸组为52±11%。当将胆酰肌氨酸（5 mmol/升）灌注到麻醉兔的结肠中时，与鹅去氧胆酸盐不同，它不会影响水的吸收或对赤藓糖醇的通透性，鹅去氧胆酸盐会引起强烈的水分泌并导致赤藓糖醇流失。我们得出结论，胆酰肌氨酸具有在缺乏状态下作为合适的胆汁酸替代物所需的物理化学和生理特性。
