INVIVO O-DE-ETHYLATION OF PHENACETIN IN 3-METHYLCHOLANTHRENE-PRETREATED RATS - GUT WALL AND LIVER 1ST-PASS METABOLISM

Abstract

By use of a high-performance liquid chromatographic procedure, phenacetin (acetophenetidin) and its O-de-ethylated metabolite paracetamol (acetaminophen) [analgesics], after hydrolysis of paracetamol conjugates, were simultaneously quantified in arterial plasma of both control and 3-methylcholanthrene-pretreated rats after the i.v., portal vein and intraduodenal administration of phenacetin. 3-Methylcholanthrene pretreatment resulted in enhanced phenacetin disposition as shown from decreased plasma half-life time, decreased oral availability, increased clearance and a raise in metabolite levels.By constructing plasma concentration-time curves and determining the areas under the curves, liver and gut wall 1st-pass metabolism were assessed. Apparently, in 3-methylcholanthrene-pretreated rats the intestine contributes significantly, and predominantly over the liver, to phenacetin 1st-pass metabolism. In contrast, gut wall metabolism in control rats could not be demonstrated.