Abstract

Propranolol binding to rat serum samples was studied after 7 days of phenobarbital (PB) administration to induce alpha-1-acid glycoprotein (AAG). In male Sprague-Dawley rats, serum AAG concentrations and the bound/free propranolol ratio (B/F) were increased slightly after enzyme-inducing drug administration (mean +/- S.D.): from 0.30 +/- 0.04 to 0.49 +/- 0.05 g/l for AAG and from 6.79 +/- 1.24 to 8.81 to 1.31 for B/F. In male DA (Dark Agouti) rats, the same parameters increased greatly: from 0.20 +/- 0.01 to 1.38 +/- 0.13 g/l for AAF and from 8.75 +/- 1.01 to 27.15 +/- 3.28 for B/F. PB concentrations determined on the same serum samples were similar in both rat strains. Female DA rats also were responsive to PB administration. Propranolol binding to DA rat serum from the treated group was characterized by an increase in high-affinity binding site concentrations. The binding of propranolol to isolated rat AAG at various concentrations (0.2-1 g/l), alone or associated with rat serum albumin at a constant concentration (36 g/l), also was studied. Propranolol binding capacities to rat AAG were increased 2.4 times by the presence of albumin and consequently B/F values for both proteins agreed with values obtained with serum samples. These results indicate that increased propranolol binding to rat serum induced by PB administration is probably a direct consequence of increased concentrations of AAG. The high sensitivity of DA rats to PB suggests that this strain should be used preferentially for the study of the effect of cytochrome P-450 inducers on AAG metabolism and cationic drug binding.