Summary
Four metabolites of dipyrone, 4-methyl-aminoantipyrine (MAA), 4-aminoantipyrine (AA), 4-formylaminoantipyrine (FAA) and 4-acetylamino-antipyrine (AAA) can be identified in human plasma after its oral administration. The plasma protein binding of the metabolites in samples from 20 healthy volunteers was determined by ultrafiltration. None of the metabolites were found to be extensively bound to plasma proteins. The binding of MAA and AA was relatively higher than of FAA and AAA, as expected from their chemical structure. The mean percentage plasma protein binding was 57.6% for MAA, 47.9 for AA, 17.8 for FAA and 14.2% for AAA. The correlation between the unbound concentration in plasma and the total concentrations of MAA, AA, FAA and AAA was linear. No association was evident between the total protein plasma concentration and the extent of binding. The possible therapeutic implications related to protein binding of several analgesic and non-steroidal anti-inflammatory drugs are discussed.
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Volz M, Kellner HM (1980) Kinetics and metabolism of pyrazolones (propyphenazone, aminopyrine and dipyrone). Br J Clin Pharmacol 10: 299S-308S
Levy M, Flusser D, Zylber-Katz E, Granit L (1984) Plasma kinetics of dipyrone metabolites in rapid and slow acetylators. Eur J Clin Pharmacol 27: 453–458
Zylber-Katz E, Granit L, Drayer DE, Levy M (1984) Simultaneous determination of dipyrone metabolites in plasma by high-performance liquid chromatography. J Chromatogr 305: 477–484
Koch-Weser J, Sellers EM (1976) Binding of drugs to serum albumin. N Engl J Med 294: 526–531
Eldor A, Zylber-Katz E, Levy M (1984) The effect of oral administration of dipyrone on the capacity of blood platelets to synthesize thromboxane A2 in man. Eur J Clin Pharmacol 26: 171–176
Simons KJ, Simons FER, Briggs CJ, Lo L (1979) Theophylline protein binding in humans. J Pharm Sci 68: 252–253
Vallner JJ (1977) Binding of drugs by albumin and plasma protein. J Pharm Sci 66: 447–465
Rowland M (1980) Plasma protein binding and therapeutic drug monitoring. Ther Drug Monit 2: 29–37
Sudlow G, Birkett DJ, Wade DN (1976) Further characterization of specific drug binding sites on human serum albumin. Molec Pharmacol 12: 1052–1061
Sjoholm I, Ekman B, Kober A, Ljungstedt-Pahlman I, Seiving B, Sjodin T (1979) Binding of drugs to human serum albumin: XI Molec Pharmacol 16: 767–777
Borga O, Piafsky KM, Nilsen OG (1977) Plasma protein binding of basic drugs. Clin Pharmacol Ther 22: 539–544
Heel RC, Avery GS (1980) Appendix A, drug data information. In: Avery GS (ed) Drug treatment. Adis Press, Sydney, New York, Churchill Livingstone, Edingburgh, London, pp 1211–1222
Levy G (1979) Pharmacokinetics of salicylate in man. Drug Metab Rev 9 [1]: 3–19
Mandelli M, Tognoni G (1980) Monitoring plasma concentration of salicylates. Clin Pharmacokinet 5: 424–440
Borga O, Odar-Cederlof I, Ringberger VA, Norlin A (1976) Protein binding of salicylate in uremic and normal plasma. Clin Pharmacol Ther 20: 464–475
Ekstrand R, Alvan G, Borga O (1979) Concentration dependent plasma protein binding of salicylate in rheumatoid patients. Clin Pharmacokinet 4: 137–143
Wosilait WD (1976) Theoretical analysis of the binding of salicylate by human serum albumin: The relationship between free and bound drug and therapeutic levels. Eur J Clin Pharmacol 9: 285–290
Kramer E, Routh JI (1973) The binding of salicylic acid and acetylsalicylic acid to human serum albumin. Clin Biochem 6: 98–105
Roberts MS, Rumble RH, Wanwimolruk S, Thomas D, Brooks PM (1983) Pharmacokinetics of aspirin and salicylate in elderly subjects and in patients with alcoholic liver disease. Eur J Clin Pharmacol 25: 253–261
Parkhouse J (1975) Simple analgesics. Drugs 10: 366–393
Shirkey HC (1980) Paediatric clinical pharmacology and therapeutics. In Avery GS (ed) Drug treatment. Adis Press, Sydney, New York, Churchill Livingstone, Edinburgh, London, pp 97–157
Koch-Weser J, Sellers EM (1971) Drug interactions with coumarin anticoagulants (second part). N Engl J Med 285: 547–558
Hansen JM, Christensen LK (1977) Drug interactions with oral sulphonylurea hypoglycaemic drugs. Drugs 13: 24–34
Hart FD (1980) Rheumatic disorders. In: Avery GS (ed) Drug treatment. Adis Press. Sydney New York, pp 846–888
Hoffbrand BI, Kininmonth DA (1967) Potentiation of anticoagulants. Br Med J 2: 838–839
Vesell ES, Passananti GT, Johnson AO (1975) Failure of indomethacin and warfarin to interact in normal human volunteers. J Clin Pharmacol 15: 486–495
Penner JA, Abbrecht PH (1975) Lack of interaction between ibuprofen and warfarin. Curr Ther Res 18: 862–871
Aarons L, Grennan DM, Siddiqui M (1983) The binding of ibuprofen to plasma proteins. Eur J Clin Pharmacol 25: 815–818
Grennan DM, Ferry DG, Ashworth ME, Kenny RE, Mackinnon M (1979) The aspirin-ibuprofen interaction in rheumatoid arthritis. Br J Clin Pharmacol 8: 497–503
Verbeeck RK, Blackburn JL, Lowen GR (1983) Clinical pharmacokinetics of non-steroidal anti-inflammatory durgs. Clin Pharmacokinet 8: 297–331
Miller DR (1981) Combination use of non-steroidal anti-inflammatory drugs. Drug Intell Clin Pharm 15: 3–7
Willis JV, Kendall MJ, Jack DB (1980) A study of the effect of aspirin on the pharmacokinetics of oral and intravenous diclofenac sodium. Eur J Clin Pharmacol 18: 415–418
Rubin A, Rodda BE, Warrick P, Gruber CM Jr, Ridolfo AS (1973) Interactions of aspirin and non-steroidal anti-inflammatory drugs in man. Arthritis Rheum 16: 635–645
Brooks PM, Khong TK (1977) Fluribiprofen — aspirin interaction: A double-blind crossover study. Curr Med Res Opin 5: 53–57
Segre EJ, Chaplin M, Forchielli E, Runkel R, Sevelius H. Naproxen — aspirin interactions in man. Clin Pharmacol Ther 15: 374–379
Forrest JAH, Clements JA, Prescott LF (1982) Clinical pharmacokinetics of paracetamol. Clin Pharmacokinet 7: 93–107
Badian M, LeNormand Y, Rupp W, Zapf R (1984) There is no interaction between dipyrone (metamizol) and the anticoagulants, phenoprocoumon and ethylbiscoumacetate, in normal caucasian subjects. Int J Pharm 18: 9–15
Banerjee NC, Miller GE, Stowe CM (1967) Excretion of aminopyrine and its metabolites into cows' milk. Toxicol Appl Pharmacol 10: 604–612
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Zylber-Katz, E., Granit, L. & Levy, M. Plasma protein binding of dipyrone metabolites in man. Eur J Clin Pharmacol 29, 67–71 (1985). https://doi.org/10.1007/BF00547371
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DOI: https://doi.org/10.1007/BF00547371