Correlation Between Antipyrine Metabolite Formation and Theophylline Metabolism in Humans After Simultaneous Single-Dose Administration and at Steady State

J Pharmacol Exp Ther. 1985 Jun;233(3):770-5.


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)

MeSH terms

  • Adult
  • Antipyrine / administration & dosage
  • Antipyrine / analogs & derivatives
  • Antipyrine / metabolism*
  • Half-Life
  • Humans
  • Kinetics
  • Male
  • Metabolic Clearance Rate
  • Theophylline / administration & dosage
  • Theophylline / metabolism*


  • 4-hydroxyantipyrine
  • 3-hydroxymethylantipyrine
  • Theophylline
  • Antipyrine