title: A Systems Model for Ursodeoxycholic Acid Metabolism in Healthy and Patients With Primary Biliary Cirrhosis.
abstract: A systems model was developed to describe the metabolism and disposition of ursodeoxycholic acid (UDCA) and its conjugates in healthy subjects based on pharmacokinetic (PK) data from published studies in order to study the distribution of oral UDCA and potential interactions influencing therapeutic effects upon interruption of its enterohepatic recirculation. The base model was empirically adapted to patients with primary biliary cirrhosis (PBC) based on current understanding of disease pathophysiology and clinical measurements. Simulations were performed for patients with PBC under two competing hypotheses: one for inhibition of ileal absorption of both UDCA and conjugates and the other only of conjugates. The simulations predicted distinctly different bile acid distribution patterns in plasma and bile. The UDCA model adapted to patients with PBC provides a platform to investigate a complex therapeutic drug interaction among UDCA, UDCA conjugates, and inhibition of ileal bile acid transport in this rare disease population.
authors.affiliation: PAREXEL International, Durham, North Carolina, USA.
authors.forename: P
authors.initials: P
authors.lastname: Zuo
authors.affiliation: Cempra Pharmaceuticals, Chapel Hill, North Carolina, USA.
authors.forename: R L
authors.initials: RL
authors.lastname: Dobbins
authors.affiliation: PAREXEL International, Durham, North Carolina, USA.
authors.forename: R L
authors.initials: RL
authors.lastname: O'Connor-Semmes
authors.affiliation: PAREXEL International, Durham, North Carolina, USA.
authors.forename: M A
authors.initials: MA
authors.lastname: Young
mesh_terms: D000284:Administration, Oral; D001647:Bile Acids and Salts / Q000378:metabolism; D002756:Cholagogues and Choleretics / Q000008:administration & dosage / Q000378:metabolism*; D016208:Databases, Factual / Q000706:statistics & numerical data; D006801:Humans; D007082:Ileum / Q000187:drug effects / Q000378:metabolism; D008105:Liver Cirrhosis, Biliary / Q000188:drug therapy / Q000378:metabolism*; D011897:Random Allocation; D013597:Systems Analysis; D014580:Ursodeoxycholic Acid / Q000008:administration & dosage / Q000378:metabolism*
chemical_list: D001647:Bile Acids and Salts; D002756:Cholagogues and Choleretics; D014580:Ursodeoxycholic Acid