Abstract

A pharmacokinetic drug interaction between propranolol and oxyphenbutazone has been found in the anesthetized dog. The administrations of dl-propranolol proloniged the half-life of oxyphenbutazone from 50.8 ± 4.9 to 66.6 ± 11.3 minutes, whereas saline was without effect. The mechanism of this interaction was investigated by administering saline or dl-propranolol (0.25 mg/kg i.v. followed by 3 µg/kg/min) during a steady-state infusion of oxyphenbutazone (20 mg/kg i.v. followed by 0.2 mg/kg/min). dl-Propranolol increased arterial oxyphenbutazone blood concentration from 51.8 ± 2.8 to 61.1 ± 3.3 µg/ml and decreased oxyphenbutazone clearance from 46.3 ± 1.9 to 39.5 ± 2.5 ml/min. Hepatic extraction of oxyphenbutazone was measured directly and was increased from 13.0 ± 4.6 to 23.1 ± 3.1%. A saline infusion produced no changes in hemodynamics or in oxyphenbutazone kinetics. This drug/drug interaction is a further example of a hemodynamic drug interaction in which beta adrenergic blockade due to dl-propranolol decreases cardiac output and liver blood flow with a resultant reduction in the rate of delivery of oxyphenbutazone to its major site of elimination in the liver. This study illustrates the general principle that the magnitude of the change in drug clearance associated with an alteration in hepatic blood flow is dependent upon the hepatic extraction of the drug. Those drugs with a low hepatic extraction are affected least because the extraction of the drug changes to compensate for the alteration in flow.