European Journal of Clinical Pharmacology

, Volume 20, Issue 2, pp 127–133 | Cite as

Ketoprofen pharmacokinetics and bioavailability based on an improved sensitive and specific assay

  • R. A. Upton
  • R. L. Williams
  • T. W. Guentert
  • J. N. Buskin
  • S. Riegelman
Originals

Summary

A commercial capsule containing 50 mg of ketoprofen (Orudis), a simple capsule containing 50 mg of ketoprofen alone and 50 mg of ketoprofen in an aqueous solution were given as separate doses in a randomized sequence to 12 normal adult males. The areas under the resulting plasma concentration-time curves (AUC) were remarkably consistent for each volunteer. The bioavailability from the commerical capsule relative to that from the solution was 99.7%±10.5% and that from the simple capsule was 102%±10%. After 6 of the volunteers had taken the commercial capsule 6 hourly for thirteen doses, their AUC extrapolated to infinity was significantly higher (by 22%) than that after the single dose indicating, contrary to previous reports, accumulation upon multiple dosing. The interdose AUC after the thirteenth dose was, however, statistically indistinguishable from the AUC-to-infinity after the single dose as might be expected from linear kinetics. The ketoprofen solution generated peak plasma concentrations in only one-third the time (21±7 min) required for the capsules (commercial, 72±45; simple, 61±39 min). Despite plasma concentrations being tracked over a 200-fold range, log linearity was not established within 12 h in any of the 42 profiles obtained. A two-compartment open model was fitted to the solution data giving excellent prediction of the time-to-peak and clearance (Cl/F=5.2±1.1 l/h) as determined by eye and by log-trapezoidal rule, respectively.

Key words

ketoprofen pharmacokinetics multipledose bioavailability assay modelling 

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References

  1. 1.
    Akaike H (1976) An information criterion (A. I. C.). Math Sci 14: 5–9Google Scholar
  2. 2.
    Anderson JA, Lee P, Webb J, Buchanan WW (1974) Evaluation of the therapeutic potential of ketoprofen in rheumatoid arthritis. Curr Med Res Opin 2: 189–197Google Scholar
  3. 3.
    Bostrom A (1979) RMEAS, a program for repeated measures analysis of variance, version 5. Scientific Computing Services, University of California, San Francisco, CA 94143 USAGoogle Scholar
  4. 4.
    Caille G, Besner J-G, Brodeur J, Vezina M (1978) Profil pharmacocinetique du ketoprofene. Ann Pharm Fr 36: 243–252Google Scholar
  5. 5.
    Castegnaro E, Iannotta F, Pollini C (1974) Ricerca preliminare sulla farmacocinetica del ketoprofen nell'uomo. Farmaco 29: 520–522Google Scholar
  6. 6.
    Chiou WL (1978) Critical evaluation of the potential error in pharmacokinetic studies of using the linear trapezoidal rule method for the calculation of the area under the plasma level-time curve. J Pharmacokin Biopharm 6: 539–546Google Scholar
  7. 7.
    Courpron P, Brazier JL, Meunier P, Ribon B, Bannier A (1978) Biodisponibilite du ketoprofene; comparaison des voies d'administration orale et rectale. Lyon Med 239: 477–482Google Scholar
  8. 8.
    Delbarre F, Roucayrol JC, Amor B, Ingrand J, Bourat G, Fournel J, Courjaret J (1976) Pharmacokinetic study of ketoprofen (19.583 R. P.) in man using the tritiated compound. Scand J Rheumatol (Suppl) 14: 45–52Google Scholar
  9. 9.
    Fossgreen J, Kirchheiner B, Petersen FO, Tophøj E, Zachariae E (1976) Clinical evaluation of ketoprofen (19.583 R. P.) in rheumatoid arthritis-double-blind cross-over comparison with indomethacin. Scand J Rheumatol (Suppl) 14: 93–98Google Scholar
  10. 10.
    Franchimont P, Cauwenberge van H (1973) Etude a double insu de l'efficacite therapeutique de profenid et de l'indomethacine dans la polyarthrite rhumatoide. Rhumatologie 177–178Google Scholar
  11. 11.
    Grahame R, Burry HC (1976) Ketoprofen — a new antirheumatic agent. Scand J Rheumatol (Suppl) 14: 133–136Google Scholar
  12. 12.
    Guentert TW, Holford NHG, Coates PE, Upton RA, Riegelman S (1979) Quinidine pharmacokinetics in man: Choice of a disposition model and absolute bioavailability studies. J Pharmacokin Biopharm 7: 315–330Google Scholar
  13. 13.
    Gyory AN, Bloch M, Burry HC, Grahame R (1972) Orudis in management of rheumatoid arthritis and osteoarthrosis of the hip: Comparison with indomethacin. Br Med J 4: 298–300Google Scholar
  14. 14.
    Holford NHG (1979) DRUGFUN, a modelling procedure available through the PROPHET data analysis system. National Institutes of Health, Washington, DC, USAGoogle Scholar
  15. 15.
    Julou L, Guyonnet JC, Ducrot R, Fournel J, Pasquet J (1976) Ketoprofen (19.583 R.P.) (2-(3-benzoyl-phenyl)-propionic acid). Main pharmacological properties — Outline of toxicological and pharmacokinetic data. Scand J Rheumatol (Suppl) 14: 33–44Google Scholar
  16. 16.
    Lewellen ORW, Templeton R (1976) The pharmacokinetics of ketoprofen in man during and after repeated oral dosing (50 mg q.i.d.) with Orudis. Scand J Rheumatol (Suppl) 14: 53–62Google Scholar
  17. 17.
    Lussier A, Camerlain M, Menard H, Mykal D, Wehner S (1976) A Double-blind cross-over evaluation of ketoprofen and aspirin in rheumatoid arthritis. Scand J Rheumatol (Suppl) 14: 99–104Google Scholar
  18. 18.
    Mitchell WS, Scott P, Kennedy AC, Brooks PM, Templeton R, Jeffries MG (1975) Clinico-pharmacological studies on ketoprofen (‘Orudis’). Curr Med Res Opin 3: 423–430Google Scholar
  19. 19.
    Nordemar R, Björklund S, Gyllenberg B, Thune S, Wallden B (1973) Clinical evaluation of ketoprofen (19.583 R. P.) in rheumatoid arthritis. Rhumatologie 179Google Scholar
  20. 20.
    Sala G, Silvestrini N, Castegnaro E, Pollini C (1978) Pharmacokinetic and therapeutic effects of ketoprofen. Farmaco 33: 455–460Google Scholar
  21. 21.
    Upton RA, Buskin JN, Guentert TW, Williams RL, Riegelman S (1980) A convenient and sensitive high performance liquid chromatography assay for ketoprofen, naproxen and other allied drugs in plasma or urine. J Chromatogr 190: 119–128Google Scholar
  22. 22.
    Upton RA, Buskin JN, Williams RL, Holford NHG, Riegelman S (1980) Negligible excretion of unchanged ketoprofen, naproxen or probenecid in urine. J Pharm Sci 69: 1254–1257Google Scholar
  23. 23.
    Vallado FF, Banos JG, Tevar JP, Gutierrez JB (1973) Estudio de la actividad antiinflammatorica del 19.583 R. P. in artritis reumatoides proables y posibles. Rhumatologie 165–167Google Scholar
  24. 24.
    Vargaftig BB, Dao N (1971) Release of vasoactive substances from guinea-pig lungs by slow-reacting substance C and arachidonic acid. Its blockade by nonsteroid anti-inflammatory agents. Pharmacology 6: 99–108Google Scholar
  25. 25.
    Viara M, Franchi R, Liverta C, Pollini C, Pontiroli AE (1975) Ketoprofen and indomethacin in the treatment of rheumatoid arthritis: A double-blind cross-over trial. Eur J Clin Pharmacol 8: 205–208Google Scholar
  26. 26.
    Yeh KC, Kwan KC (1978) A comparison of numerical integrating algorithms by trapezoidal, lagrange and spline approximation. J Pharmacokin Biopharm 6: 79–98Google Scholar
  27. 27.
    Zutshi D, Stern D, Bloch M, Mason RM (1974) Ketoprofen: A double-blind cross-over study with indomethacin in patients with rheumatoid arthritis. Rheumatol Rehabil 13: 10–16Google Scholar
  28. 28.
    Zutshi D, Mason M (1976) Ketoprofen in rheumatoid arthritis: Its tolerance and therapeutic effect. Scand J Rheumatol (Suppl) 14: 77–84Google Scholar

Copyright information

© Springer-Verlag 1981

Authors and Affiliations

  • R. A. Upton
    • 1
  • R. L. Williams
    • 1
  • T. W. Guentert
    • 1
  • J. N. Buskin
    • 1
  • S. Riegelman
    • 1
  1. 1.School of PharmacyUniversity of California, San FranciscoSan FranciscoUSA

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