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 . A method of treating or ameliorating primary sclerosing cholangitis (PSC) 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. 
       
     
     
         2 . The method of  claim 1 , wherein the ASBTI decreases serum bile acid or hepatic bile acid levels in the patient by at least 20%. 
     
     
         3 . The method of  claim 1 , wherein less than 10% of the ASBTI is systemically absorbed. 
     
     
         4 .- 19 . (canceled) 
     
     
         20 . The method of  claim 1 , wherein the dosage of the ASBTI is between about 1 μg/kg/day and about 10 mg/kg/day. 
     
     
         21 . The method of  claim 1 , wherein the dosage of the ASBTI is any dosage from about 5 μg/kg/day to about 1 mg/kg/day. 
     
     
         22 . The method of  claim 1 , wherein the dosage of the ASBTI is any dosage from about 10 μg/kg/day to about 300 μg/kg/day. 
     
     
         23 . The method of  claim 1 , wherein the dosage comprises between 0.1 to 20 mg of the ASBTI. 
     
     
         24 .- 38 . (canceled) 
     
     
         39 . The method of  claim 1 , 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. 
     
     
         40 . The method of  claim 1 , wherein the ASBTI decreases elevated levels of lipoprotein X; elevated levels of AP (alkaline phosphatase); elevated levels of LAP (leukocyte alkaline phosphatase); elevated levels of gamma GT (gamma-glutamyl transpeptidase); elevated levels of 5′-nucleotidase; pruritus; elevated serum concentration of conjugated bilirubin; elevated serum concentrations of nonconjugated bilirubin or delta bilirubin; and presence of xanthomas. 
     
     
         41 . (canceled) 
     
     
         42 . The method of  claim 1 , wherein PSC is characterized by one or more symptoms selected from jaundice, pruritis, cirrhosis, hypercholemia, neonatal respiratory distress syndrome, lung pneumonia, increased serum concentration of bile acids, increased serum concentration of bilirubin, hepatocellular injury, liver scarring, liver failure, hepatomegaly, xanthomas, malabsorption, splenomegaly, diarrhea, pancreatitis, hepatocellular necrosis, giant cell formation, hepatocellular careinoma, gastrointestinal bleeding, portal hypertension, hearing loss, fatigue, loss of appetite, anorexia, peculiar smell, dark urine, light stools, steatorrhea, failure to thrive, renal failure, fibrosis, obstruction of medium sized intra- and extrahepatic ductuli, and obstruction of large sized intra- and extrahepatic ductuli. 
     
     
         43 . (canceled) 
     
     
         44 . The method of  claim 1 , further comprises 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. 
     
     
         45 . The method of  claim 1 , wherein the ASBTI is administered before ingestion of food, optionally wherein the ASBTI is administered less than about 60 minutes or less than about 30 minutes before ingestion of food. 
     
     
         46 . The method of  claim 1 , wherein the ASBTI is administered orally. 
     
     
         47 . The method of  claim 1 , wherein the ASBTI is administered as an ileal-pH sensitive release or an enterically coated formulation. 
     
     
         48 . The method of  claim 1 , further comprising a vitamin supplement. 
     
     
         49 . The method of  claim 48 , wherein the vitamin supplement comprises a fat-soluble vitamin. 
     
     
         50 . The method of  claim 49 , wherein the fat-soluble vitamin is vitamin A, D, E, or K. 
     
     
         51 . The method of  claim 1 , further comprising an agent selected from the group consisting of cholestyramine, antihistamine, rifampin, nalaxone, Phenobarbital, dronabinol, methotrexate, corticosteroid, cyclosporine, and colchicines. 
     
     
         52 . The method of  claim 1 , further comprising the use of partial external biliary diversion (PEBD). 
     
     
         53 . The method of  claim 1 , wherein the individual in need thereof is nonresponsive to ursodiol. 
     
     
         54 . (canceled) 
     
     
         55 . The method of  claim 1 , further comprising a bile acid sequestrant or binder. 
     
     
         56 . The method of  claim 1 , wherein the ASBTI decreases pruritus. 
     
     
         57 . A method of treating or ameliorating primary sclerosing cholangitis (PSC) 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. 
       
     
     
         58 . The method of  claim 57 , wherein the ASBTI decreases serum bile acid or hepatic bile acid levels in the patient by at least 20%. 
     
     
         59 . The method of  claim 57 , wherein less than 10% of the ASBTI is systemically absorbed. 
     
     
         60 . The method of  claim 57 , wherein the dosage of the ASBTI is between about 1 μg/kg/day and about 10 mg/kg/day. 
     
     
         61 . The method of  claim 57 , 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 arehitecture. 
     
     
         62 . The method of  claim 57 , wherein the ASBTI decreases pruritus. 
     
     
         63 . A method of treating or ameliorating primary sclerosing cholangitis (PSC) comprising administering to an individual in need thereof a therapeutically effective amount of an Apical Sodium-dependent Bile Acid Transporter Inhibitor (ASBTI) 1,1-dioxo-3,3-dibutyl-5-phenyl -7-methylthio-8-(N-{(R)-α-[N-((S)-1-carboxypropyl)carbamoyl]benzyl}carbamoylmethoxy)-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepine, or a pharmaceutically acceptable salt thereof. 
     
     
         64 . The method of  claim 63 , wherein less than 10% of the ASBTI is systemically absorbed. 
     
     
         65 . The method of  claim 63 , wherein the dosage of the ASBTI is between about 1 μg/kg/day and about 10 mg/kg/day. 
     
     
         66 . The method of  claim 63 , 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 arehitecture. 
     
     
         67 . The method of  claim 63 , wherein the ASBTI decreases pruritus.