Bile acid recycling inhibitors for treatment of hypercholemia and cholestatic liver disease

Abstract

Provided herein are methods of treating or ameliorating hypercholemia or a cholestatic liver disease by administering to an individual in need thereof a therapeutically effective amount of an Apical Sodium-dependent Bile Acid Transporter Inhibitor (ASBTI) or a pharmaceutically acceptable salt thereof. Also provided are methods for treating or ameliorating a liver disease, decreasing the levels of serum bile acids or hepatic bile acids, treating or ameliorating pruritis, reducing liver enzymes, or reducing bilirubin comprising administering to an individual in need thereof a therapeutically effective amount of ASBTI or a pharmaceutically acceptable salt thereof.

1 .- 55 . (canceled) 
     
     
         56 . A method of treating or ameliorating intrahepatic cholestasis of pregnancy (ICP) comprising administering to an individual in need thereof a therapeutically effective amount of an Apical Sodium-dependent Bile Acid Transporter Inhibitor (ASBTI) having a structure 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof. 
       
     
     
         57 . The method of  claim 56 , wherein the ASBTI is 
       
         
           
           
               
               
           
         
       
     
     
         58 . The method of  claim 56 , wherein the ASBTI decreases serum bile acid or hepatic bile acid levels in the patient by at least 20%. 
     
     
         59 . The method of  claim 58 , wherein the ASBTI decreases serum bile acid or hepatic bile acid levels in the patient by at least 30%. 
     
     
         60 . The method of  claim 58 , wherein the ASBTI decreases serum bile acid or hepatic bile acid levels in the patient by at least 40%. 
     
     
         61 . The method of  claim 56 , wherein less than 10% of the ASBTI is systemically absorbed upon oral administration. 
     
     
         62 . The method of  claim 56 , wherein the ASBTI is administered at a dosage between about 1 μg/kg/day and about 10 mg/kg/day. 
     
     
         63 . The method of  claim 56 , wherein the ASBTI is administered at a dosage from about 5 μg/kg/day to about 1 mg/kg/day. 
     
     
         64 . The method of  claim 56 , wherein the ASBTI is administered at a dosage from about 10 μg/kg/day to about 300 μg/kg/day. 
     
     
         65 . The method of  claim 56 , wherein the ASBTI is administered at a dosage comprising from about 0.1 mg to about 40 mg of the ASBTI. 
     
     
         66 . The method of  claim 56 , wherein the ASBTI decreases the levels of serum bile acids or hepatic bile acids, reduces bilirubin, reduces liver enzymes, lowers intraenterocyte bile acids/salts, or reduces necrosis and/or damage to hepatocellular architecture. 
     
     
         67 . The method of  claim 56 , wherein the ASBTI decreases pruritus. 
     
     
         68 . The method of  claim 56 , wherein the ICP is in the second or third trimester of pregnancy. 
     
     
         69 . The method of  claim 56 , wherein the ICP is characterized by one or more of pruritis, biochemical cholestasis, or cholestatic liver disease. 
     
     
         70 . The method of  claim 56 , wherein the ASBTI is administered with a second agent selected from a bile acid sequestrant or binder. 
     
     
         71 . The method of  claim 56 , wherein the ASBTI is administered with a second agent selected from ursodeoxycholic acid, chenodeoxycholic acid, cholic acid, taurocholic acid, ursocholic acid, glycocholic acid, glycodeoxycholic acid, taurodeoxycholic acid, taurocholate, glycochenodeoxycholic acid, and tauroursodeoxycholic acid. 
     
     
         72 . The method of  claim 56 , wherein the ASBTI is administered before ingestion of food. 
     
     
         73 . The method of  claim 71 , wherein the ASBTI is administered less than about 60 minutes or less than about 30 minutes before ingestion of food 
     
     
         74 . The method of  claim 56 , wherein the ASBTI is administered orally. 
     
     
         75 . The method of  claim 56 , wherein the ASBTI is administered as an ileal-pH sensitive release or an enterically coated formulation. 
     
     
         76 . The method of  claim 56 , wherein the ASBTI is administered with a vitamin supplement. 
     
     
         77 . The method of  claim 76 , wherein the vitamin supplement comprises a fat-soluble vitamin. 
     
     
         78 . The method of  claim 77 , wherein the fat-soluble vitamin is selected from the group consisting of vitamin A, D, E, or K. 
     
     
         79 . The method of  claim 56 , wherein the individual in need thereof is nonresponsive to ursodiol. 
     
     
         80 . The method of  claim 56 , wherein the treatment reduces the risk for prematurity and/or intrauterine fetal death.