Effect of pregnenolone carbonitrile, promethazine and antipyrine pretreatment on antipyrine metabolite formation in rats.

The effect of three inducers of cytochrome P-450-mediated drug oxidations (Pregnenolone carbonitrile, promethazine and antipyrine) on antipyrine metabolite kinetics has been investigated using the urinary metabolite pattern and 14CO2 exhalation rate (CER)-time profile following [N-methyl-14C]antipyrine administration. The CER-time profiles showed the characteristic changes associated with induction, namely, increased maximum CER and decreased half-life, previously observed in phenobarbitone and beta-naphthaflavone-induced rats. Calculation of formation rate constants based on urinary recovery of 3-hydroxymethyl-, 4-hydroxy- and nor-antipyrine indicated no clear selectivity of induction by any pretreatment. However, the percentage increase of the latter two metabolites was two- to four-fold greater than for the former metabolite. The use of the metabolite ratio (3-hydroxymethylantipyrine/norantipyrine) is proposed to assess the qualitative nature of induction of antipyrine metabolism.