European Journal of Clinical Pharmacology

, Volume 28, Issue 5, pp 589–595 | Cite as

Antipyrine metabolite formation and excretion in patients with chronic renal failure

  • M. W. E. Teunissen
  • D. Kampf
  • I. Roots
  • N. P. E. Vermeulen
  • D. D. Breimer
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Summary

In the present study the influence of chronic renal insufficiency on antipyrine clearance, metabolite formation and excretion was investigated in 8 patients. After oral administration of antipyrine, the parent compound, its metabolites and their conjugates were assayed in plasma and urine. Besides the parent drug, 3-hydroxymethylantipyrine (HMA) was present in plasma in the free and conjugated forms, whereas 4-hydroxyantipyrine (OHA) and norantipyrine (NORA) were found only in the conjugated form. The same was true for urine. The plasma concentrations of these metabolites are too low to be measured in subjects with normal renal function.

Plasma antipyrine clearance in the patients was in the same range as in healthy subjects. Investigation of metabolite kinetics, however, revealed that the rate of formation of NORA was preferentially decreased, whereas that of OHA and HMA were unaltered. Renal clearance of the metabolites of antipyrine was severely impaired in patients with renal insufficiency, and the resulting accumulation made it possible for the first-time to measure the antipyrine metabolites in plasma. Mean residence times of metabolites were longer than that of the parent compound. Renal clearances of the conjugates were correlated with the creatinine clearance, but were somewhat higher. Renal clearance of free HMA was lower and was also correlated with creatinine clearance.

The mean clearance for glucuronidation of HMA was 93.1 ml/min. The results suggest that in healthy subjects Phase I metabolism is the rate-limiting step in the elimination of antipyrine, which is essential for its application as a model drug in metabolism studies.

Key words

antipyrine chronic renal failure drug metabolism metabolism cumulation renal excretion pharmacokinetics clearance 
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References

  1. 1.
    Bässmann H, Böttcher J (1980) New phase I and phase II metabolites of phenazone. Naunyn Schmiedeberg's Arch Pharmacol 311 (Suppl): R 17Google Scholar
  2. 2.
    Benet LZ, Galeazzi RL (1979) Non-compartmental determination of the steady state volume of distribution. J Pharm Sci 168: 1071–1074Google Scholar
  3. 3.
    Bennett WM, Muther RS, Parker RA, Feig P, Morrison G, Golper TA, Singer I (1980) Drug therapy in renal failure: dosing guidelines for adults. Ann Intern Med 93: 62–89 and 286–325Google Scholar
  4. 4.
    Böttcher J, Bässmann H, Schüppel R (1981) Direct quantitation of urinary conjugates of 3-14C-antipyrine metabolism in man. Naunyn Schmiedeberg's Arch Pharmacol 316 (Suppl): R 5Google Scholar
  5. 5.
    Breimer DD (1983) Individual variations in drug disposition. Clinical implications and methods of investigations. Clin Pharmacokinet 8: 371–377Google Scholar
  6. 6.
    Danhof M, Krom DP, Breimer DD (1979a) Studies on the different metabolic pathways of antipyrine in rats: Influence of phenobarbital and 3-methylcholanthrene treatment. Xenobiotica 9: 695–702Google Scholar
  7. 7.
    Danhof M, de Groot-Van der Vis E, Breimer DD (1979b) Assay of antipyrine and its primary metabolites in plasma, saliva and urine by high performance liquid chromatography and some preliminary results in man. Pharmacology 18: 210–223Google Scholar
  8. 8.
    Danhof M, Verbeek RMA, Van Boxtel CJ, Boeijinga KJ, Breimer DD (1982a) Differential effects of enzyme induction on antipyrine metabolite formation. Br J Clin Pharmacol 13: 379–386Google Scholar
  9. 9.
    Danhof M, Teunissen MWE, Breimer DD (1982b) 3-Hydroxymethylantipyrine excretion in urine: A reconsideration of previously published data and synthesis of reference substance. Pharmacology 24: 181–184Google Scholar
  10. 10.
    Danhof M, Van Zuilen A, Boeijinga JK, Breimer DD (1982c) Studies on the different metabolic pathways of antipyrine in man: oral versus i.v. administration and the influence of urinary collection time. Eur J Clin Pharmacol 21: 433–441Google Scholar
  11. 11.
    Dettli L (1976) Drug dosage in renal disease. Clin Pharmacokinet 1: 126–134Google Scholar
  12. 12.
    Harman AW, Penhall RK, Priestly BG, Frewin DB, Phillips PJ, Clarkson AR (1977) Salivary antipyrine kinetics in hepatic and renal disease and in patients on anticonvulsant therapy. Aust NZ J Med 7: 385–390Google Scholar
  13. 13.
    Kampf D, Roots I, Hildebrandt AG (1980) Urinary excretion of D-glucaric acid, an indicator of drug metabolizing enzyme activity, in patients with impaired renal function. Eur J Clin Pharmacol 18: 255–261Google Scholar
  14. 14.
    Koike E, Iida H, Okauna M, Kashioka A (1954) Organic pigments. II. Synthesis of 1-phenyl-3-methyl-5-pyrazolone and its derivatives. J Chem Soc Jpn 57, 56–58Google Scholar
  15. 15.
    Lichter M, Black M, Arias IM (1973) The metabolism of antipyrine in patients with chronic renal failure. J Pharmacol Exp Ther 187: 612–619Google Scholar
  16. 16.
    Maddocks JL, Wake CJ, Harber MJ (1975) The plasma half-life of antipyrine in chronic uraemic and normal subjects. Br J Clin Pharmacol 2: 339–343Google Scholar
  17. 17.
    Németh I, Szeleczki T (1981) Enhanced drug metabolism and renal dysfunction. Br J Clin Pharmacol 11: 92–93Google Scholar
  18. 18.
    Pschorr R (1897) Ueber das 1-phenyl-2,3-dimethyl-4-oxy-5-pyrazolon (4-oxyantipyrin). Justus Liebigs Ann Chem 293: 49–55Google Scholar
  19. 19.
    Reidenberg MM (1977) The biotransformation of drugs in renal failure. Am J Med 62: 482–485Google Scholar
  20. 20.
    Simon P, Meyrier A, Brissot P (1981) Uremia and the liver. II. Drugs and the liver in the uremic patient. Nephron 29: 7–13Google Scholar
  21. 21.
    Teunissen MWE, Joeres RP, Vermeulen NPE, Breimer DD (1983a) Influence of 9-hydroxyellipticine and 3-methylcholanthrene treatment on in vivo antipyrine metabolite formation in rats. Xenobiotica 13: 223–231Google Scholar
  22. 22.
    Teunissen MWE, Meerburg-van der Torren JE, Breimer DD (1983b) Automated HPLC-determination of antipyrine and its main metabolites in plasma, saliva and urine, including 4,4′-hydroxyantipyrine. J Chromatogr 278: 367–378Google Scholar
  23. 23.
    Teunissen MWE, Spoelstra P, Koch CW, Eeda B, van Duyn W, Janssens AR, Breimer DD (1984) Antipyrine clearance and metabolite formation in patients with alcoholic cirrhosis. Br J Clin Pharmacol 18: 707–715Google Scholar
  24. 24.
    Toverud EL, Boobis AR, Brodie MJ, Murray S, Bennett PN, Whitmarsh V, Davies DS (1981) Differential induction of antipyrine metabolism by rifampicin. Eur J Clin Pharmacol 21: 155–160Google Scholar
  25. 25.
    Verbeeck RK (1982) Glucuronidation and disposition of drug glucuronides in patients with renal failure. Drug Metabol Disposit 10: 87–89Google Scholar
  26. 26.
    Verbeeck RK, Branch RA, Wilkinson GR (1981) Drug metabolites and renal failure: Pharmacokinetic and clinical implications. Clin Pharmacokinet 6: 329–345Google Scholar
  27. 27.
    Vesell ES (1977) Genetic and environmental factors affecting drug disposition in man. Clin Pharmacol Ther 22: 659–679Google Scholar
  28. 28.
    Vesell ES, Passananti GT, Glenwright PA, Dvorchik BH (1975) Studies on the disposition of antipyrine, aminopyrine and phenacetin using plasma, saliva and urine. Clin Pharmacol Ther 18: 259–272Google Scholar
  29. 29.
    Vestal RE, Norris AH, Tobin JD, Cohen BH, Shock NW, Andres R (1975) Antipyrine metabolism in man: influence of age, caffeine and smoking. Clin Pharmacol Ther 18: 425–432Google Scholar
  30. 30.
    Wittemann G, Schüppel R (1968) Nachweis eines neuen reaktionsfähigen Metaboliten im Stoffwechsel von Phenazon (Antipyrin). Naunyn Schmiedeberg's Arch Pharmacol 260: 219–220Google Scholar
  31. 31.
    Yoshimura H, Shimeno H, Tsukamoto H (1971) Metabolism of drugs. LXX. Further study on antipyrine metabolism. Chem Pharm Bull Tokyo 19: 41–45Google Scholar

Copyright information

© Springer-Verlag 1985

Authors and Affiliations

  • M. W. E. Teunissen
    • 1
  • D. Kampf
    • 2
  • I. Roots
    • 3
  • N. P. E. Vermeulen
    • 1
  • D. D. Breimer
    • 1
  1. 1.Department of Pharmacology, Subfaculty of Pharmacy, Sylvius LaboratoriesUniversity of LeidenLeidenThe Netherlands
  2. 2.Department of Internal Medicine (Nephrology Unit), Klinikum CharlottenburgFree University of BerlinBerlin
  3. 3.Department of Clinical Pharmacology, Klinikum SteglitzFree University of BerlinBerlin

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