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. 1990 Apr;29(4):381–389. doi: 10.1111/j.1365-2125.1990.tb03654.x

The effect of multiple dosage on the kinetics of glucuronidation and sulphation of diflunisal in man.

R K Verbeeck 1, G R Loewen 1, J I MacDonald 1, R J Herman 1
PMCID: PMC1380106  PMID: 2328191

Abstract

1. The single (250 and 500 mg) and multiple dose (250 and 500 mg twice daily for 15 days) pharmacokinetics of diflunisal were compared in young volunteers. 2. The plasma clearance of diflunisal was lowered significantly after multiple dose administration (5.2 +/- 1.2 and 4.2 +/- 0.7 ml min-1 for the 250 and 500 mg twice daily regimens, respectively) as compared with single dose administration 11.4 +/- 3.1 and 9.9 +/- 2.0 ml min-1 for the 250 and 500 mg single doses, respectively). 3. The partial metabolic clearances of diflunisal by acyl and phenolic glucuronide formation were lowered significantly (greater than 50%) after multiple dose administration. 4. The urinary recovery of diflunisal sulphate increased as a function of dose: 6.1 +/- 2.8 and 9.1 +/- 3.5% following the 250 and 500 mg single dose, respectively, and 10.9 +/- 3.1 and 15.9 +/- 3.6% following the 250 and 500 mg twice daily regimens. The partial metabolic clearance of diflunisal by sulphate conjugation was unchanged following multiple dose administration. 5. The plasma protein binding of diflunisal was concentration-dependent. Analysis of unbound plasma clearances of diflunisal showed that its total plasma clearance following 500 mg twice daily was affected by both saturable glucuronidation and concentration-dependent plasma binding.

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Selected References

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  1. Bjornsson T. D., Shand D. G. Estimation of kinetic parameters from a two-point determination of the drug cumulation factor. Clin Pharmacol Ther. 1979 Nov;26(5):540–547. doi: 10.1002/cpt1979265540. [DOI] [PubMed] [Google Scholar]
  2. Davies R. O. Review of the animal and clinical pharmacology of diflunisal. Pharmacotherapy. 1983 Mar-Apr;3(2 Pt 2):9S–22S. [PubMed] [Google Scholar]
  3. Dickinson R. G., King A. R. Reactivity considerations in the analysis of glucuronide and sulfate conjugates of diflunisal. Ther Drug Monit. 1989 Nov;11(6):712–720. doi: 10.1097/00007691-198911000-00018. [DOI] [PubMed] [Google Scholar]
  4. Erikson L. O., Wåhlin-Boll E., Odar-Cederlöf I., Lindholm L., Melander A. Influence of renal failure, rheumatoid arthritis and old age on the pharmacokinetics of diflunisal. Eur J Clin Pharmacol. 1989;36(2):165–174. doi: 10.1007/BF00609190. [DOI] [PubMed] [Google Scholar]
  5. Faed E. M. Properties of acyl glucuronides: implications for studies of the pharmacokinetics and metabolism of acidic drugs. Drug Metab Rev. 1984;15(5-6):1213–1249. doi: 10.3109/03602538409033562. [DOI] [PubMed] [Google Scholar]
  6. Furst D. E., Tozer T. N., Melmon K. L. Salicylate clearance, the resultant of protein binding and metabolism. Clin Pharmacol Ther. 1979 Sep;26(3):380–389. doi: 10.1002/cpt1979263380. [DOI] [PubMed] [Google Scholar]
  7. Hansen-Møller J., Cornett C., Dalgaard L., Honoré Hansen S. Isolation and identification of the rearrangement products of diflunisal 1-O-acyl glucuronide. J Pharm Biomed Anal. 1988;6(3):229–240. doi: 10.1016/0731-7085(88)80049-9. [DOI] [PubMed] [Google Scholar]
  8. Houston J. B. Drug metabolite kinetics. Pharmacol Ther. 1981;15(3):521–552. doi: 10.1016/0163-7258(81)90056-5. [DOI] [PubMed] [Google Scholar]
  9. Hyneck M. L., Smith P. C., Munafo A., McDonagh A. F., Benet L. Z. Disposition and irreversible plasma protein binding of tolmetin in humans. Clin Pharmacol Ther. 1988 Jul;44(1):107–114. doi: 10.1038/clpt.1988.120. [DOI] [PubMed] [Google Scholar]
  10. Langendijk P. N., Smith P. C., Hasegawa J., Benet L. Z. Simultaneous determination of zomepirac and its major metabolite zomepirac glucuronide in human plasma and urine. J Chromatogr. 1984 May 11;307(2):371–379. doi: 10.1016/s0378-4347(00)84108-0. [DOI] [PubMed] [Google Scholar]
  11. Lin J. H., Hooke K. F., Yeh K. C., Duggan D. E. Dose-dependent pharmacokinetics of diflunisal in rats: dual effects of protein binding and metabolism. J Pharmacol Exp Ther. 1985 Nov;235(2):402–406. [PubMed] [Google Scholar]
  12. Loewen G. R., Herman R. J., Ross S. G., Verbeeck R. K. Effect of dose on the glucuronidation and sulphation kinetics of diflunisal in man: single dose studies. Br J Clin Pharmacol. 1988 Jul;26(1):31–39. doi: 10.1111/j.1365-2125.1988.tb03360.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  13. Loewen G. R., Macdonald J. I., Verbeeck R. K. High-performance liquid chromatographic method for the simultaneous quantitation of diflunisal and its glucuronide and sulfate conjugates in human urine. J Pharm Sci. 1989 Mar;78(3):250–255. doi: 10.1002/jps.2600780317. [DOI] [PubMed] [Google Scholar]
  14. Loewen G. R., McKay G., Verbeeck R. K. Isolation and identification of a new major metabolite of diflunisal in man. The sulfate conjugate. Drug Metab Dispos. 1986 Jan-Feb;14(1):127–131. [PubMed] [Google Scholar]
  15. Meffin P. J., Brooks P. M., Bertouch J., Veenendaal J. R., Harrington B. J. Diflunisal disposition and hypouricemic response in osteoarthritis. Clin Pharmacol Ther. 1983 Jun;33(6):813–821. doi: 10.1038/clpt.1983.111. [DOI] [PubMed] [Google Scholar]
  16. Musson D. G., Lin J. H., Lyon K. A., Tocco D. J., Yeh K. C. Assay methodology for quantification of the ester and ether glucuronide conjugates of diflunisal in human urine. J Chromatogr. 1985 Feb 8;337(2):363–378. doi: 10.1016/0378-4347(85)80049-9. [DOI] [PubMed] [Google Scholar]
  17. Tocco D. J., Breault G. O., Zacchei A. G., Steelman S. L., Perrier C. V. Physiological disposition and metabolism of 5-(2',4'-difluorophenyl)salicyclic acid, a new salicylate. Drug Metab Dispos. 1975 Nov-Dec;3(6):453–466. [PubMed] [Google Scholar]
  18. Verbeeck R. K., Boel A., Buntinx A., De Schepper P. J. Plasma protein binding and interaction studies with diflunisal, a new salicylate analgesic. Biochem Pharmacol. 1980 Feb 15;29(4):571–576. doi: 10.1016/0006-2952(80)90378-0. [DOI] [PubMed] [Google Scholar]
  19. Verbeeck R. K., Dickinson R. G., Pond S. M. Biliary excretion of diflunisal conjugates in patients with T-tube drainage. Eur J Clin Pharmacol. 1988;34(4):423–426. doi: 10.1007/BF00542448. [DOI] [PubMed] [Google Scholar]
  20. Verbeeck R., Tjandramaga T. B., Mullie A., Verbesselt R., Verberckmoes R., de Schepper P. J. Biotransformation of diflunisal and renal excretion of its glucuronides in renal insufficiency. Br J Clin Pharmacol. 1979 Mar;7(3):273–282. doi: 10.1111/j.1365-2125.1979.tb00932.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  21. Wilkinson G. R., Shand D. G. Commentary: a physiological approach to hepatic drug clearance. Clin Pharmacol Ther. 1975 Oct;18(4):377–390. doi: 10.1002/cpt1975184377. [DOI] [PubMed] [Google Scholar]

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