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.
Highlights
The bioavailability and clearance of drugs primarily metabolized by the liver can be affected by liver cirrhosis [1,2,3]
In the current study of propranolol pharmacokinetics after iv and oral administration in patients with liver cirrhosis and healthy controls there was a linear correlation between fasting serum bile acids (SBA) concentration and propranolol exposure
The study findings confirmed those reported in previous studies, namely that clearance after intravenous administration is reduced [16], plasma concentrations after oral administration are higher [17,18] and that the heart rate response to oral propranolol is greater in patients than controls [18]
Summary
The bioavailability and clearance of drugs primarily metabolized by the liver can be affected by liver cirrhosis [1,2,3]. This is especially true for drugs which have a high hepatic extraction (high-extraction drugs) [1,4]. The clearance of high-extraction drugs, which is grossly determined by blood (or plasma) flow across the liver [1,2,3], may be reduced in cirrhosis as a result of impaired blood flow [8,9]. In contrast to increased porto-systemic shunting which only affects the pharmacokinetics of orally administered drugs, impaired drug clearance affects the pharmacokinetics of both orally and intravenously administered drugs and can prolong the exposure to high drug concentrations, thereby increasing the risk of toxicity
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