A study of factors influencing drug disposition in chronic liver disease, using the model drug (+)-propranolol

Abstract

The pharmacokinetics, following i.v. administration of (+)-propranolol (40 mg) have been compared to in vitro measurement of protein binding and biochemical parameters of liver function in six normal subjects and twenty patients with stable chronic liver disease. The clearance of (+)-propranolol decreased with evidence of increasing severity of impairment of liver function correlating significantly with a fall in serum albumin, a rise in bilirubin and a prolongation in prothrombin index. The clearance of (+)-propranolol correlated with and was numerically similar to the clearance of indocyanine green in normal subjects and also in patients with chronic liver disease. Protein binding was decreased in chronic liver disease, but this change was not related to changes in plasma proteins. In normal subjects and patients without ascites the volume of distribution increased with decreases in protein binding. Ascites was associated with a further increase in the volume of distribution. The considerable variation in half-life largely depends on changes in liver blood flow, the degree of protein binding and the plasma protein pool size.