Correlation between antipyrine metabolite formation and theophylline metabolism in humans after simultaneous single-dose administration and at steady state.
To nine healthy male volunteers two model substrates for oxidative drug-metabolizing enzyme activity, viz, antipyrine (A) and theophylline (T) were administered simultaneously by the p.o. route. To six of them, the same two drugs were also 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 two 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 also 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).(ABSTRACT TRUNCATED AT 250 WORDS)
D000328:Adult; D000983:Antipyrine / Q000008:administration & dosage / Q000031:analogs & derivatives / Q000378:metabolism*; D006207:Half-Life; D006801:Humans; D007700:Kinetics; D008297:Male; D008657:Metabolic Clearance Rate; D013806:Theophylline / Q000008:administration & dosage / Q000378:metabolism*
C007983:4-hydroxyantipyrine; C031820:3-hydroxymethylantipyrine; D013806:Theophylline; D000983:Antipyrine