Effect of altered plasma protein binding on pharmacokinetics and pharmacodynamics of propranolol in rats after surgery: role of alpha-1-acid glycoprotein.

The pharmacokinetics and pharmacodynamics of propranolol in rats 2 days after laparotomy were compared to control animals. The apparent volumes of distribution and the systemic clearance of propranolol were decreased to about 20 to 40 and 70% of control values, respectively. The area under the blood concentration-time curve (AUC) of propranolol after p.o. administration showed a marked elevation after surgery and its availability increased about 2-fold at doses of 5.0 and 12.5 mg/kg. These changes were associated with a decreased plasma unbound fraction of propranolol after surgery. Immunological determination of alpha-1-acid glycoprotein (AGP) revealed a marked increase after laparotomy and a linear relationship was found between the plasma AGP concentration and the binding capacity of high-affinity binding site for propranolol in plasma (r = 0.961, P less than .001). AUC of p.o. administered propranolol was also correlated with plasma AGP concentration. The beta-blocking activity of propranolol assessed by the reduction in the isoproterenol-induced tachycardia was decreased in rats after laparotomy when it was evaluated in terms of the total plasma concentration of propranolol. In contrast, its activity evaluated by the unbound plasma concentration showed no difference between control and laparotomized rats, suggesting the dependence of the pharmacological activity of propranolol on its unbound level in plasma. Thus, laparotomy-induced changes in both pharmacokinetics and pharmacodynamics could be considered largely due to an increase in its binding to the increased plasma level of AGP.