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.

Pathogenesis of Hepatic Encephalopathy in Chronic Liver Disease

“…5 Serum BAs are higher in cirrhotic patients than in controls because of reduced hepatic BA clearance. 69 Moreover, serum, CSF, and brain BAs were enhanced in patients who died of fulminant hepatic failure, while such effects were related to coma duration and brain edema in 50% of patients. 68 Nevertheless, clinical trials to explore the role of BAs in cirrhotic patients with and without HE are needed to elucidate the role of BAs in the development of HE.…”

Beta‐blockers in patients with advanced liver disease: Has the dust settled?

“…This might be particularly important during a situation of increased physiologic stress, such as sepsis, which is a frequent event in cirrhosis. In addition, propranolol is mainly metabolized by the liver and, therefore, as liver function deteriorates, its bioavailability can increase significantly, whereas nadolol is excreted unchanged in urine, and its bioavailability increases with kidney dysfunction . For all these reasons, doses of NSBBs need to be re‐evaluated on a periodic basis.…”

Development and Evaluation of a Physiologically Based Pharmacokinetic Drug-Disease Model of Propranolol for Suggesting Model Informed Dosing in Liver Cirrhosis Patients

“…This argument can be further verified by comparison of the mean observed clearance (CL) 0.82 L/h/kg (95% CI: 0.64-1.00) [26][27][28]46,47 with mean predicted clearance 0.99 L/h/kg (95% CI: 0.70-1.2) after IV administration. Similarly, CL/F in healthy individuals was also comparable, as its observed and reported values were 217 L/h (95% CI: 183.6-250.80) 26,[29][30][31][32][33]46,[48][49][50][51][52] and 183.3 L/h (95% CI: 169.9-196.6), respectively. Furthermore, the AFE value for CL (0.83 and 1.15 after IV and oral dose predictions) strengthened the argument that the developed PBPK model was predicting the disposition of the drug precisely (Table 4).…”