Influence of 9-hydroxyellipticine and 3-methylcholanthrene treatment on antipyrine metabolite formation in rats in vivo.

The influence of pretreatment of rats with 9-hydroxyellipticine and 3-methylcholanthrene on different enzymes of the hepatic mixed-function oxidase system were studied using antipyrine as model compound. Antipyrine half-lives and clearances were estimated in blood, and the metabolite profile was determined in urine. 3-Methylcholanthrene treatment resulted in an increase in antipyrine clearance from 17 to 75 ml/min per kg. Partial clearance of formation of 4-hydroxyantipyrine was selectively increased from 3.9 to 28.2 ml/min kg, whereas clearance of 3-hydroxymethylantipyrine was decreased from 3.2 to 1.2 ml/min per kg. Norantipyrine formation was increased from 2.7 to 7.2 ml/min per kg, while 4,4'-dihydroxyantipyrine formation was unchanged. 9-Hydroxyellipticine treatment resulted in no change in the total clearance, and only the clearance of 4,4'-dihydroxyantipyrine was decreased, from 2.5 to 1.5 ml/min per kg. After pretreatment with 3-methylcholanthrene, 9-hydroxyellipticine treatment resulted in a selective decrease in the clearances of 4-hydroxyantipyrine, from 28.2 to 15.8 ml/min per kg, and of 4,4'-hydroxyantipyrine, from 3.8 to 1.6 ml/min per kg. From these results it is concluded, that 9-hydroxyellipticine is a selective inhibitor of the activity of some of the cytochrome P-450s involved in antipyrine metabolism, though this inhibition does not effect all of these enzymes, nor is it restricted to polycyclic hydrocarbon-induced activity. These results further substantiate the value of antipyrine as a model substrate, for they indicate that the formation of all four metabolites of antipyrine in rats is mediated by different (iso-)enzymes.