SC-435, an Inhibitor of ASBT, Improves Liver Function in a Rat Partial Bile Duct Ligation Model of Cholestasis
Bradley T Keller, Svetlana Nikoulino, Nicolaus Nazarenkov, Bronislovo Gedulin
Lumena Pharmaceuticals' Son Diego, CA
Blocking bile acid absorption in the intestine is an effective approach to reducing the pool of serum bile acids (SBA). Thus, inhibiting the ileal bile acid transporter ASBT is being considered as a new treatment for cholestatic liver diseases. We report the effect of SC-435, a potent, minimally absorbed ASBT inhibitor (ASBTi) on liver function parameters in a rat partial bile duct ligation (pBDL) model of cholestasis. We adapted a previously described mouse pBDL model (Heinrich et al., Surgery 2011) to create a model in HSD rats which displays key characteristics of cholestatic liver disease - markedly elevated serum bile acids and liver function markers. Rats were anesthetized with isoflurane, the common bile duct exposed by midline laparotomy and a short length of PE-10 tubing placed parallel to the bile duct. A ligature of 4-0 silk suture was tied tightly around the duct and tubing after which the tubing was removed resulting in constriction of the duct lumen without complete obstruction. Three days after pBDL surgery, the serum liver alkaline phosphatase (ALP), aspartate aminotransferase (AST), alanine aminotransferase (ALT) and ۷-glutamyl transferase (GGT) increased from baseline by 5. 3, 5. 7, 5. 3 and 12. 1-fold respectively. Serum total bilirubin (TBil) levels increased by ≥100-fold. Seven days after surgery, AST and ALT levels had begun to normalize (3. 0 and 1. 7-fold) while ALP, GGT and total bilirubin values remained high at 4. 9, 22 and 103-fold compared to sham controls. This profile was sustained at 14 days post-surgery with elevations of 6. 8-fold for ALP, 15. 5-fold for GGT and 128-fold for TBil. SBA were also dramatically increased by 28.9-fold (30 uM to 873 uM) 7 days after surgery. SC-435 was administered to the test group by once daily oral gavage at 10 mg/kg starting one day prior to pBDL surgery. Seven days after surgery ASBTi treatment had significantly reduced ALP by 58%, GGT by 48%, TBil by 49% and SBA by 52% compared to the untreated control group (p < 0.03 for all parameters). By 14 days post-surgery, ALP was reduced 75%, GGT by 65% and TBil by 67% compared to the untreated control group (p < 0.05 for all parameters). CONCLUSIONS: The pBDL model in HSD rats results in significant increases in SBA and serum liver enzymes from 3 to 14 days after surgery that are characteristic of cholestasis and liver injury. Blocking bile acid recycling with SC-435 prevents dramatic increases in total SBA and liver biomarkers suggesting that an ASBTi may provide a new therapeutic option for the treatment of cholestatic liver disease by decreasing the accumulation of toxic bile acids and reducing the severity of cholestatic liver injury.
Bradley T. Keller - Employment: Lumena Pharmaceuticals, Rivervest Venture Partners
Bronislava Gedulin - Employment: Lumena Pharmaceuticals
The following people have nothing to disclose: Svetlana Nikoulina, Nicolaus Nazarenkov