Absorption and Elimination Profile of Isoproterenol III: The Metabolic Fate of dl-Isoproterenol-7-3H in the Dog

Abstract

Intravenous injection of isoproterenol-7-3H in dogs, in doses ranging from 0.4 to 1.6 mcg./kg. body weight, immediately induced tachycardia which declined with a half-life of about 1 min. The resulting levels of radioactivity in blood declined with a significantly longer half-life of 3–4 min. Unchanged isoproterenol accounted for less than 1 percent of the total radioactivity in plasma after intravenous medication. After oral administration of 15 mg. of isoproterenol-7-3H hydrochloride to dogs, a biphasic time course was observed for both heart rate and radioactivity in blood with maxima occurring at 0.5 and 1–2 hr. after medication. The metabolic fate of isoproterenol was determined by the route of medication, the intravenous and intraportal route giving rise mainly to 3-O-methyliso-proterenol, while oral medication was converted mainly to a sulfuric acid ester which was formed either by the intestinal flora or during passage through the intestinal wall. The rapid decrease in tachycardia after intravenous medication is consistent with the rapid conversion of the drug to inactive metabolites while the more prolonged tachycardia induced by oral medication results from slow absorption. Intravenous injection of isoproterenol-7-3H in dogs, in doses ranging from 0.4 to 1.6 mcg./kg. body weight, immediately induced tachycardia which declined with a half-life of about 1 min. The resulting levels of radioactivity in blood declined with a significantly longer half-life of 3–4 min. Unchanged isoproterenol accounted for less than 1 percent of the total radioactivity in plasma after intravenous medication. After oral administration of 15 mg. of isoproterenol-7-3H hydrochloride to dogs, a biphasic time course was observed for both heart rate and radioactivity in blood with maxima occurring at 0.5 and 1–2 hr. after medication. The metabolic fate of isoproterenol was determined by the route of medication, the intravenous and intraportal route giving rise mainly to 3-O-methyliso-proterenol, while oral medication was converted mainly to a sulfuric acid ester which was formed either by the intestinal flora or during passage through the intestinal wall. The rapid decrease in tachycardia after intravenous medication is consistent with the rapid conversion of the drug to inactive metabolites while the more prolonged tachycardia induced by oral medication results from slow absorption.