This article describes the effects of chronically administered phenobarbital (180 mg/day p.o.) in dogs on the bioavailability of single 40-mg oral doses of propranolol and on the pharmacokinetics and the patterns of propranolol metabolism in urine after both oral (40 mg) and i.v. (6 mg) doses. Phenobarbital decreased the bioavailability of propranolol from 7.7 to 3.5%. By using a gas chromatography/mass spectrometry technique, the quantitative metabolic pattern of i.v. propranolol was unaltered by phenobarbital, but increases in hydroxylation and induction of new metabolites were observed for oral propranolol after phenobarbital treatment. Chronic phenobarbital treatment led to significant decreases in the half-lives of propranolol after both i.v. and oral doses. Little change was observed in the hepatic blood flow, systemic clearance or intrinsic oral clearance. These data demonstrate the completely nonrestrictive elimination of propranolol. With phenobarbital, both the extent of plasma protein binding and the distribution into erythrocytes change significantly, yet the overall clearance remains unaltered. The half-lives fell in responses to the binding-induced reduction in the apparent volume of distribution.