CONTRIBUTION OF THE SMALL-INTESTINE TO THE FIRST-PASS UPTAKE AND SYSTEMIC CLEARANCE OF PROPRANOLOL IN RABBITS

Epithelial cells of the intestine enclose isozymes able to metabolize propranolol, raising the possibility that the gut contributes with the liver to the first-pass uptake and systemic clearance of propranolol. To assess the role of the liver in the first-pass uptake, propranolol was injected into the jugular vein and a mesenteric vein of anestheti zed New Zealand rabbits, and blood samples were drawn from the abdomin al aorta, or it was injected into the intestine and samples were drawn simultaneously from the portal vein and the abdominal aorta. Extracti on of propranolol by the liver was estimated to be 96-97%. To assess t he intestinal extraction of oral propranolol, a porto-cava transpositi on was conducted in two groups of animals, and propranolol was injecte d into the first 30 cm of the small intestine or into the jugular vein and samples were withdrawn from the abdominal aorta; propranolol extr action by the intestine was 43%. To document the contribution of the i ntestine in the systemic clearance of propranolol, propranolol was inj ected into the jugular vein and blood samples were drawn simultaneousl y from the abdominal aorta (before the gut) and from the portal vein ( after the gut); propranolol extraction from the systemic circulation b y the intestine was 24%. Only the liver generated detectable amounts o f conjugated metabolites of propranolol. In the in vitro studies, it w as shown that propranolol was rapidly metabolized by the liver, yieldi ng 4-hydroxypropranolol and conjugates of propranolol; propranolol met abolism in the proximal small intestine was slower and yielded only 4- hydroxypropranolol. Hydroxylation activity of the small intestine decr eased by a factor of 20 in distal segments (150-180 cm). It is conclud ed that the intestine contributes to the first-pass uptake and to the systemic clearance of propranolol, essentially conducting a ring oxida tion of propranolol.