title: A study of the relationship between serum bile acids and propranolol pharmacokinetics and pharmacodynamics in patients with liver cirrhosis and in healthy controls.
abstract: The main objectives of the study were to determine the exposure and bioavailability of oral propranolol and to investigate their associations with serum bile acid concentration in patients with liver cirrhosis and in healthy controls. A further objective was to study the pharmacodynamics of propranolol. An open-label crossover study was performed to determine the pharmacokinetics and pharmacodynamics of propranolol after oral (40 mg) and intravenous (1 mg) administration as well as the concentration of total and individual fasting serum bile acids in 15 patients with liver cirrhosis and 5 healthy controls. After intravenous propranolol, patients showed a 1.8-fold increase in the area under the plasma concentration-time curve (AUC0-∞), a 1.8-fold increase in volume of distribution and a 3-fold increase in the elimination half-life (mean ± SEM: 641±100 vs. 205±43 minutes) compared to controls. After oral application, AUC0-∞ and elimination half-life of propranolol were increased 6- and 4-fold, respectively, and bioavailability 3-fold (83±8 vs. 27±9.2%). Maximal effects on blood pressure and heart rate occurred during the first 4 and first 2 hours, respectively, after intravenous and oral application in both patients and controls. Total serum bile acid concentrations were higher in patients than controls (42±11 vs. 2.7±0.3 µmol/L) and were linearly correlated with the serum chenodeoxycholic acid concentration. There was a linear correlation between the SBA concentration and propranolol oral AUC0-∞ in subjects not receiving interacting drugs (r2 = 0.73, n = 18). The bioavailability of and exposure to oral propranolol are increased in patients with cirrhosis. Fasting serum bile acid concentration may be helpful in predicting the exposure to oral propranolol in these patients.
authors.affiliation: Division of Clinical Pharmacology & Toxicology, University and University Hospital Basel, Basel, Switzerland.
authors.forename: Anne B
authors.initials: AB
authors.lastname: Taegtmeyer
authors.affiliation: Division of Clinical Pharmacology & Toxicology, University and University Hospital Basel, Basel, Switzerland; Department of Biomedicine, University of Basel, Basel, Switzerland.
authors.forename: Manuel
authors.initials: M
authors.lastname: Haschke
authors.affiliation: Division of Clinical Pharmacology & Toxicology, University and University Hospital Basel, Basel, Switzerland.
authors.forename: Lydia
authors.initials: L
authors.lastname: Tchambaz
authors.affiliation: Division of Clinical Pharmacology & Toxicology, University and University Hospital Basel, Basel, Switzerland.
authors.forename: Mirabel
authors.initials: M
authors.lastname: Buylaert
authors.affiliation: Division of Clinical Pharmacology & Toxicology, University and University Hospital Basel, Basel, Switzerland.
authors.forename: Martin
authors.initials: M
authors.lastname: Tschöpl
authors.affiliation: Department of Gastroenterology & Hepatology, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands.
authors.forename: Ulrich
authors.initials: U
authors.lastname: Beuers
authors.affiliation: Division of Clinical Pharmacology & Toxicology, University and University Hospital Basel, Basel, Switzerland; Department of Biomedicine, University of Basel, Basel, Switzerland.
authors.forename: Jürgen
authors.initials: J
authors.lastname: Drewe
authors.affiliation: Division of Clinical Pharmacology & Toxicology, University and University Hospital Basel, Basel, Switzerland; Department of Biomedicine, University of Basel, Basel, Switzerland.
authors.forename: Stephan
authors.initials: S
authors.lastname: Krähenbühl
mesh_terms: D061605:Administration, Intravenous; D000284:Administration, Oral; D000328:Adult; D001647:Bile Acids and Salts / Q000097:blood*; D018592:Cross-Over Studies; D005260:Female; D006801:Humans; D008103:Liver Cirrhosis / Q000097:blood*; D008297:Male; D008875:Middle Aged; D011433:Propranolol / Q000008:administration & dosage / Q000097:blood*
chemical_list: D001647:Bile Acids and Salts; D011433:Propranolol