Galactosylated Pro-Drug of Ursodeoxycholic Acid: Design, Synthesis, Characterization, and Pharmacological Effects in a Rat Model of Estrogen-Induced Cholestasis.

  title={Galactosylated Pro-Drug of Ursodeoxycholic Acid: Design, Synthesis, Characterization, and Pharmacological Effects in a Rat Model of Estrogen-Induced Cholestasis.},
  author={Francesca Di Guida and Claudio Pirozzi and Salvatore Magliocca and Anna Santoro and Adriano Lama and Roberto Russo and Maria Nieddu and Lucia Burrai and Gianpiero Boatto and Maria Pina Mollica and Federica Sodano and Loretta Lazzarato and Konstantin Chegaev and Rosaria Meli and Giuseppina Mattace Raso and Maria Grazia Rimoli},
  journal={Molecular pharmaceutics},
  volume={15 1},
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… Expand
Hepatoprotection of auraptene from the peels of citrus fruits against 17α-ethinylestradiol-induced cholestasis in mice by activating farnesoid X receptor.
Auraptene alleviated EE-induced cholestasis due to FXR-mediated gene regulation, and the changes in transporters and enzymes, as well as ameliorated liver histology by auraptene, were abrogated by the FXR antagonist guggulsterone. Expand
Paracetamol-Galactose Conjugate: A Novel Pro-drug for an Old Analgesic Drug.
The synthesised and characterised Paracetamol galactosylated pro-drug (PARgal) shows a range of physicochemical properties, solubility, lipophilicity and chemical stability at differing physiological pH values and in human serum, and support the use of galactose as a suitable carrier in the development of pro- drugs for analgesic treatment. Expand
Synthesis, cytotoxicity and liver targeting of 3‐O‐β‐D‐Galactosylated Resveratrol
3‐O‐β‐D‐Galactosylated Resveratrol (Gal‐Res) was synthesized by structural modification of Res to enhance bioavailability and liver targeting. Expand
Management of Intrahepatic Cholestasis of Pregnancy: Recommendations of the Working Group on Obstetrics and Prenatal Medicine – Section on Maternal Disorders
Intrahepatic cholestasis of pregnancy (ICP) is the most common liver disease specific to pregnancy and a concomitant elevated level of bile acids in the serum and/or alanine aminotransferase (ALT) are suggestive for the diagnosis. Expand
Glyceric Prodrug of Ursodeoxycholic Acid (UDCA): Novozym 435-Catalyzed Synthesis of UDCA-Monoglyceride
Bile acids (BAs) are a family of steroids synthesized from cholesterol in the liver. Among bile acids, ursodeoxycholic acid (UDCA) is the drug of choice for treating primary biliary cirrhosis andExpand


Ursodeoxycholate Reduces Ethinylestradiol Glucuronidation in the Rat: Role in Prevention of Estrogen-Induced Cholestasis
Both in vivo and in vitro experiments indicate that UDC decreased the metabolic pathways involved in EE glucuronidation, hence decreasing the formation of the cholestatic derivative EE 17β-glucuronide. Expand
Protective effect of dehydroandrographolide on obstructive cholestasis in bile duct-ligated mice
DA treatment protected against liver damage and fibrosis following BDL and might be an effective therapy for extrahepatic cholestasis due to bile duct obstruction. Expand
Galactosyl prodrug of palmitoylethanolamide: synthesis, stability, cell permeation and cytoprotective activity.
  • Elvira Luongo, R. Russo, +11 authors M. G. Rimoli
  • Chemistry, Medicine
  • European journal of pharmaceutical sciences : official journal of the European Federation for Pharmaceutical Sciences
  • 2014
The synthesis of a new galactosyl prodrug of PEA, the palmitoylethanolamide-succinamyl-D-galactos-6'-yl ester (PEAGAL), which demonstrates the better efficacy of PEAGAL compared to PEA and its higher cell permeation. Expand
3alpha-6alpha-Dihydroxy-7alpha-fluoro-5beta-cholanoate (UPF-680), physicochemical and physiological properties of a new fluorinated bile acid that prevents 17alpha-ethynyl-estradiol-induced cholestasis in rats.
UPF-680 prevented 17EE-induced cholestasis and enriched the biliary bile acid pool with less detergent and cytotoxic bile acids, which may have potential in the treatment ofCholestatic liver disease. Expand
D-galactose as a vector for prodrug design.
The broad spectrum of possibilities for exploiting D-galactose as a vector for prodrug design and the synthetic strategies that allow its realization are described. Expand
The rat canalicular conjugate export pump (Mrp2) is down-regulated in intrahepatic and obstructive cholestasis.
Down-regulation of Mrp2 expression may explain impaired biliary excretion of amphiphilic anionic conjugates in these models of cholestasis. Expand
The transport and efflux of glycosylated luteinising hormone-releasing hormone analogues in caco-2 cell model: contributions of glucose transporters and efflux systems.
It is demonstrated that the transport of the glycosylated peptides was facilitated through glucose transporters, and the proportion of glucose and lactose derivatives pumped out by efflux pumps did not affect the Papp values of the analogues. Expand
Role of MRP2 and GSH in intrahepatic cycling of toxins.
Mrp2-mediated biliary secretion of GS-ANIT is a prerequisite for development of cholestasis in rats and it is hypothesized that the toxic parent compound ANIT is regenerated in the biliary tree where it can exert its toxic properties on bile duct epithelial cells. Expand
Galactosyl derivative of Nω‐nitro‐L‐arginine: Study of antiproliferative activity on human thyroid follicular carcinoma cells
The synthesis of the galactosyl ester prodrug of Nω‐nitro‐L‐arginine, NAGAL, a prodrug capable of inhibiting NOS more efficiently and with fewer adverse events than its parent drug is reported for the first time. Expand
Expression of the rat liver Na+/taurocholate cotransporter is regulated in vivo by retention of biliary constituents but not their depletion
The results indicate that ntcp is constitutively expressed and remains uneffected by either depletion or increased flux of biliary constituents, consistent with the concept that hepatocytes may be protected from bile acid toxicity during cholestasis by this mechanism. Expand