Interactions of phenobarbital with propranolol in the dog. 1. Plasma protein binding

A new drug interaction is described in which the plasma binding of propranolol is markedly stimulated by chronic phenobarbital administration in dogs. After 3 weeks of phenobarbital therapy, the percentages of unbound propranolol fell from 15.2 +/- 1.2 (mean +/- S.E.) to 2.4 +/- 0.3 (P less than .001). The time course of the induction and recovery of the binding of propranolol was also investigated. A half-maximal stimulation of binding was seen by day 3 of phenobarbital therapy and a plateau was reached after 2 weeks. After discontinuing phenobarbital, the recovery was delayed with the midpoint of the return to a normal binding value occurring on day 17. A new model of the time course for induction which includes the pharmacokinetics of the inducing agent has been developed. The stimulation of protein production by phenobarbital is assumed to follow Michaelis-Menten kinetics, but with a lag phase for the expression of the induction. Using this model, the Km for phenobarbital-stimulated production of the binding protein was 1200 ng/ml, the turnover T1/2 of the protein was 3.4 days and the T1/2 for the lag phase was also 3.4 days. The increased plasma protein binding was highly correlated (r = 0.97) with the elevated concentration of nonprecipitable glycoproteins. This most likely represents induction of alpha-1 acid glycoprotein which is the principal binding protein of propranolol in man. The plasma binding of propranolol was also stimulated with chronic phenytoin in these dogs and with a single dose of Arochlor 1254 in rats.