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

• Published in: Molecular pharmaceutics 2018-01, Vol.15 (1), p.21-30
• Main Authors: Di Guida, Francesca, Pirozzi, Claudio, Magliocca, Salvatore, Santoro, Anna, Lama, Adriano, Russo, Roberto, Nieddu, Maria, Burrai, Lucia, Boatto, Gianpiero, Mollica, Maria Pina, Sodano, Federica, Lazzarato, Loretta, Chegaev, Konstantin, Meli, Rosaria, Raso, Giuseppina Mattace, Rimoli, Maria Grazia
• Format: Article
• Language: English
• Subjects: Animals; Cholestasis - drug therapy; Cholestasis - metabolism; Cyclooxygenase 2 - blood; Estrogens - toxicity; Ethinyl Estradiol - toxicity; Hep G2 Cells; Humans; Interleukin-1beta - blood; Male; Multidrug Resistance-Associated Proteins - blood; Prodrugs - chemical synthesis; Prodrugs - chemistry; Prodrugs - therapeutic use; Rats; Rats, Wistar; Solubility; Tumor Necrosis Factor-alpha - blood; Ursodeoxycholic Acid - chemical synthesis; Ursodeoxycholic Acid - chemistry; Ursodeoxycholic Acid - therapeutic use
• ISSN: 1543-8384; 1543-8392
• DOI: 10.1021/acs.molpharmaceut.7b00626

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.