Nonlinear first-pass metabolism of propranolol in the rat.

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Abstract
The mean hepatic extraction ratio .**GRAPHIC**. 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 i.v., 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 1st pass through the liver .**GRAPHIC**. and that of the drug after escaping the hepatic 1st-pass metabolism .**GRAPHIC**. were assessed by simultaneous administration of intraportal unlabeled propranolol and i.v. 14C-propranolol over a 50 min period. Consequently, a relation of .**GRAPHIC**. < .**GRAPHIC**. < .**GRAPHIC**. was observed in higher propranolol doses, if .**GRAPHIC**. 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 1st-pass metabolism was discussed. The unusual AUC[area under the concentration-time curve]-dose relationship of propranolol reported previously in the rat could be explained on the basis of both the nonlinear hepatic 1st-pass metabolism and the nonlinear hepatic metabolism of the drug surviving the hepatic 1st-pass metabolism.