Nonlinear first-pass metabolism of propranolol in the rat.

The mean hepatic extraction ratio (ER) of propranolol depending on the inflowing blood concentration to the liver was estimated directly by simultaneous measurements of arterial, hepatoportal, and hepatic venous blood concentrations of the drug following intravenous, intraportal, and intraduodenal administration in the rat. It was shown that the inflowing blood concentration to the liver caused considerable variation depending on the route of administration. The mean hepatic extraction ratio of propranolol in the first pass through the liver (ER)fipv and that of the drug after escaping the hepatic first-pass metabolism (ER)ripv were assessed by simultaneous administration of intraportal unlabelled propranolol and intravenous 14C-propranolol over a 50-min period. Consequently, a relation of (ER)fipv less than (ER)ipv less than (ER)ripv was observed in higher propranolol doses, if (ER)ipv refers to the overall mean hepatic extraction ratio following intraportal administration of propranolol. The fraction of orally administered dose reaching the systemic circulation for a drug exhibiting nonlinear hepatic first-pass metabolism was discussed. The unusual AUC-dose relationship of propranolol reported previously in the rat could be explained on the basis of both the nonlinear hepatic first-pass metabolism and the nonlinear hepatic metabolism of drug surviving the hepatic first-pass metabolism.