Influence of allylisopropylacetamide and phenobarbital treatment on in vivo antipyrine metabolite formation in rats

The influence of pretreatment with allylisopropylacetamide (AIA) and phenobarbital (PB) on the pharmacokinetics and metabolite profile of antipyrine was studied in rats in vivo. Antipyrine concentrations were measured in blood and urine, and four metabolites (4-hydroxyantipyrine, norantipyrine, 3-hydroxymethylantipyrine and 4,4'-dihydroxyantipyrine) were determined in urine. Treatment with PB increased antipyrine blood clearance from 11.1 to 59.1 ml/min per kg. The clearances for production of metabolites all increased between four- and five-fold, indicating non-selective induction. Treatment with AIA resulted in a reduction of antipyrine clearance to 5.6 ml/min per kg. The clearances to all four metabolites were decreased to about the same extent (52-65% of control values) indicating non-selective inhibition. Treatment with AIA after PB treatment strongly inhibited drug-metabolizing enzyme activity. Blood clearance of antipyrine was reduced from 59.1 to 12.3 ml/min per kg. Clearances to the metabolites were again inhibited non-selectively (to 20-28% of PB-induced values). In contrast to previous reports, AIA in this study inhibited non-induced oxidative microsomal enzyme activity. This inhibition closely resembled AIA inhibition of PB-induced cytochromes. Therefore it is concluded that in untreated rats antipyrine is predominantly metabolized by PB-types of cytochrome P-450.