Effect of Obeticholic Acid (INT-747, Intercept) on the Hepatobiliary Transport of Bile Acids in Patients With PBC Examined by 11C-cholyl-sarcosine PET/CT

Background

Primary biliary cholangitis (PBC) is a chronic autoimmune liver disease characterized by cholestasis and cirrhosis. Pathogenesis comprises impaired hepatobiliary secretion of bile acids to the bile. As a result bile flow reduces and diminished content of bile acids in the intestines leads to impaired absorption of lipids and lipid-soluble vitamins, diarrhea, general pruritus, and fatigue.

Bile acids are transported from blood to hepatocytes by the transporter proteins Na+-taurocholate co-transporting polypeptide (NTCP) and Organic anion-transporting polypeptide (OATP) and secreted from hepatocyte to bile canaliculi by the Bile salt export pump (BSEP) and Multidrug resistance protein type 3 (MDR3). Dysfunction of BSEP most probably plays a key pathogenic role in PBC.

Ursodeoxycholic acid (UDCA) is a dihydroxylated bile acid and the only approved drug for treatment of PBC today. In most cases UDCA can delay or prevent disease progression. However, a subgroup of patients does not respond adequately to UDCA and for these patients new therapies are needed.

BSEP is induced by the nuclear bile acid receptor (BAR), also known as farnesoid X receptor (FXR). Obeticholic Acid (INT-747, Intercept) (OCA) is a FXR agonist and induces BSEP.