Alterations in serum protein binding and pharmacokinetics of l-propranolol in the rat elicited by the presence of an indwelling venous catheter.

Preliminary investigations in the rat revealed some unexpected alterations in the pharmacokinetics of l-propranolol when single dose studies were performed on two separate occasions 7 days apart. The apparent volume of distribution of l-propranolol was found to be consistently lower on the second study day. Also, the systemic availability of orally administered propranolol (6 mg/kg) increased from 4.1 to 7.8% from the 1st to the 2nd study day, indicating a decrease in the presystemic clearance of the drug. These changes were associated with a 50 to 60% decrease in the serum unbound fraction of l-propranolol between the 2 study days. Further investigations revealed that the time-dependent increase in the serum protein binding of l-propranolol was elicited by the presence of an indwelling venous catheter which was surgically implanted for the purpose of blood sampling. In contrast, a slight decrease in the serum protein binding of an acidic drug, phenytoin, was observed after catheter implantation. These changes in serum drug protein binding were readily reversed when the indwelling catheter was removed. The total serum protein concentration was not affected by catheter implantation. Fractionation of serum proteins by electrophoresis revealed an increase in alpha 1- and gamma-globulin fractions, a slight decrease in serum albumin and no change in beta- and alpha 2-globulin fractions. Competitive protein binding studies with tris(2-butoxyethyl)phosphate, a specific ligand to alpha 1-acid glycoprotein (AAG), indicate that the increase in serum l-propranolol binding was largely due to an elevation in serum AAG. These observations also explain the opposite effect of catheterization on the serum protein binding of phenytoin, which is bound largely to serum albumin.(ABSTRACT TRUNCATED AT 250 WORDS)