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The ability of isolated rat livers and lungs to clear circulating benzo(a)pyrene was examined under conditions of altered perfusion and pretreatment with 3-methylcholanthrene (3-MC). In isolated organs from control rats, pulmonary benzo(a)pyrene clearance was low (approximately 1 ml/min) and independent of flow between 10 and 45 ml/min, whereas hepatic clearance was greater and flow dependent, increasing from 3.2 +/- 0.2 ml/min at a flow of 7 ml/min to 13.2 +/- 0.7 ml/min at a flow of 20 ml/min. 3-MC pretreatment increased markedly the arylhydrocarbon hydroxylase activity of broken cell preparations from both organs. However, clearance of benzo(a)pyrene was not increased in isolated livers by 3-MC pretreatment. On the other hand, clearance did increase and became flow dependent in isolated lungs of 3-MC-pretreated rats. In fact, when organs from these animals were perfused at flows occurring in vivo, hepatic and pulmonary clearance were about equal. These results indicate that flow and metabolic capacity are important determinants of both hepatic and pulmonary clearance of xenobiotic compounds and suggest that alterations in either factor may affect the relative roles of these organs in the total body disposition of xenobiotic compounds.

By use of a high-performance liquid chromatographic procedure, phenacetin (acetophenetidin) and its O-de-ethylated metabolite paracetamol (acetaminophen), 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 was 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, it was possible to assess liver and gut wall first-pass metabolism. It is concluded that in 3-methylcholanthrene-pretreated rats the intestine contributes significantly, and predominantly over the liver, to phenacetin first-pass metabolism. In contrast, gut wall metabolism in control rats could not be demonstrated.