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Galactosylated Pro–Drug of Ursodeoxycholic Acid: Design, Synthesis, Characterization, and Pharmacological Effects in a Rat Model of Estrogen-Induced Cholestasis
- Source :
- Molecular Pharmaceutics. 15:21-30
- Publication Year :
- 2017
- Publisher :
- American Chemical Society (ACS), 2017.
-
Abstract
- 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.
- Subjects :
- Male
UDCAgal
0301 basic medicine
medicine.medical_specialty
Interleukin-1beta
ethinyl estradiol induced cholestasis
Pharmaceutical Science
Ethinyl Estradiol
03 medical and health sciences
0302 clinical medicine
Cholestasis
Internal medicine
Ethinylestradiol
Drug Discovery
medicine
Animals
Humans
Potency
Prodrugs
Rats, Wistar
Tumor Necrosis Factor-alpha
Chemistry
Drug Discovery3003 Pharmaceutical Science
Ursodeoxycholic Acid
pro-drug approach
solubility enhancement
Molecular Medicine
3003
Estrogens
Transporter
Hep G2 Cells
Prodrug
medicine.disease
Bile Salt Export Pump
Multidrug Resistance-Associated Protein 2
Ursodeoxycholic acid
Rats
030104 developmental biology
Endocrinology
Solubility
Cyclooxygenase 2
030211 gastroenterology & hepatology
Efflux
Multidrug Resistance-Associated Proteins
UDCAgal, pro-drug approach, solubility enhancement, ethinyl estradiol induced cholestasis
medicine.drug
Subjects
Details
- ISSN :
- 15438392 and 15438384
- Volume :
- 15
- Database :
- OpenAIRE
- Journal :
- Molecular Pharmaceutics
- Accession number :
- edsair.doi.dedup.....f5557d1556864f20cf148eb5522e54e5