Ursodeoxycholic acid (UDCA) is considered the first-choice therapy for cholestatic disorders. To enhance solubility and exploit specific transporters in liver, we synthesized a new galactosyl pro-drug of UDCA (UDCAgal). Ethinylestradiol (EE)-induced cholestasis was used to study and compare the effects of UDCAgal with UDCA on bile flow, hepatic canalicular efflux transporter expression, and inflammation. UDCAgal resulted quite stable both at pH 7.4 and 1.2 and regenerated the parent drug after incubation in human plasma. Its solubility, higher than UDCA, was pH- and temperature-independent. UDCAgal displayed a higher cell permeation compared to UDCA in liver HepG2 cells. Moreover, in cholestatic rats, UDCAgal showed a higher potency compared to UDCA in reducing serum biomarkers (AST, ALT, and ALP) and cytokines (TNF-α and IL-1β). The higher effect of UDCAgal on the increase in bile salt export pump and multidrug resistance-associated protein 2 transcription indicated an improved spillover of bile acids from the liver. UDCAgal showed a reduction in CCL2, as well as TNF-α, IL-1β, and cyclooxygeanse-2 mRNAs, indicating a reduction in hepatic neutrophil accumulation and inflammation. Moreover, UDCAgal, similarly to UDCA, heightens bile flow and modulates biliary acids secretion. These results indicate that UDCAgal has a potential in the treatment of cholestatic disease.

中文翻译：

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熊去氧胆酸半乳糖基化前药：在雌激素诱导的胆汁淤积大鼠模型中的设计，合成，表征和药理作用。

熊去氧胆酸（UDCA）被认为是胆汁淤积性疾病的首选疗法。为了提高溶解度并利用肝脏中的特定转运蛋白，我们合成了一种新的UDCA半乳糖基前药（UDCAgal）。乙炔雌二醇（EE）引起的胆汁淤积用于研究和比较UDCAgal和UDCA对胆汁流量，肝小管外排转运蛋白表达和炎症的影响。UDCAgal在pH 7.4和1.2下均相当稳定，并在人血浆中孵育后再生了母体药物。它的溶解度高于UDCA，与pH和温度无关。与UDCA相比，UDCAgal在肝HepG2细胞中显示出更高的细胞渗透性。此外，在胆汁淤积的大鼠中，UDCAgal与UDCA相比在降低血清生物标志物（AST，ALT和ALP）和细胞因子（TNF-α和IL-1β）方面显示出更高的效力。UDCAgal对胆盐输出泵和多药耐药相关蛋白2转录增加的较高影响表明胆汁酸从肝脏的溢出改善。UDCAgal显示CCL2以及TNF-α，IL-1β和cyclooxygeanse-2 mRNA减少，表明肝脏中性粒细胞积聚和炎症减少。此外，UDCAgal与UDCA相似，可提高胆汁流量并调节胆汁酸分泌。这些结果表明UDCAgal在胆汁淤积性疾病的治疗中具有潜力。提示肝中性粒细胞积聚和炎症减少。此外，UDCAgal与UDCA相似，可提高胆汁流量并调节胆汁酸分泌。这些结果表明UDCAgal在胆汁淤积性疾病的治疗中具有潜力。提示肝中性粒细胞积聚和炎症减少。此外，UDCAgal与UDCA相似，可提高胆汁流量并调节胆汁酸分泌。这些结果表明UDCAgal在胆汁淤积性疾病的治疗中具有潜力。