CORRELATION BETWEEN ANTIPYRINE METABOLITE FORMATION AND THEOPHYLLINE METABOLISM IN HUMANS AFTER SIMULTANEOUS SINGLE-DOSE ADMINISTRATION AND AT STEADY-STATE

Abstract

Two model substrates for oxidative drug-metabolizing enzyme activity, antipyrine (A) and theophylline (T) were administered simultaneously by the p.o. route to 9 healthy male volunteers. To 6 of them, the same 2 drugs were administered simultaneously at zero-order rate with an osmotic rectal drug delivery system in order to obtain steady-state plasma concentrations. Plasma A and T concentrations were measured simultaneously by a high-performance liquid chromatographic method and urinary excretions of the major metabolites arising from A (4-hydroxyantipyrine, norantipyrine and 3-hydroxymethylantipyrine) and from T (3-methylxanthine, 1-methyluric acid and 1,3-methyluric acid) were also measured by high-performance liquid chromatography. Correlations between total plasma clearance and metabolic clearances of A and T and clearances for production of the various metabolites were investigated in order to determine whether the metabolic pathways of A and T are mediated by the same or closely related forms of the cytochrome P-450 system. Total plasma clearances of the 2 drugs were found to correlate reasonably well (r = 0.72) but not well enough to be of useful predictive value. The strongest correlations (r = 0.91) were found between the clearance for production of 4-hydroxyantipyrine and both total and metabolic clearances of T. The clearances for production of all metabolites of T correlated better with the clearance for production of 4-hydroxyantipyrine (r ranging from 0.79-0.86) than with the clearance of norantipyrine and 3-hydroxymethylantipyrine (r ranging from 0.42-0.58). Total T metabolism and the formation of 4-hydroxyantipyrine in healthy subjects are mediated by closely related or the same forms(s) of the cytochrome P-450 system. Simultaneous administration of model substrates, particularly considering their various pathways of biotransformation, proved to be a powerful approach in correlating drug metabolism in vivo.