European Journal of Clinical Pharmacology

, Volume 38, Issue 5, pp 493–497 | Cite as

Pharmacokinetics of S(+)- and R(−)-ibuprofen in volunteers and first clinical experience of S(+)-ibuprofen in rheumatoid arthritis

  • G. Geisslinger
  • O. Schuster
  • K. -P. Stock
  • D. Loew
  • G. L. Bach
  • K. Brune
Originals

Summary

S(+)-, R(−)- or racemic ibuprofen was administered orally to volunteers in doses of 150 mg, 300 mg and 500 mg pure S(+)-, 300 mg pure R(−)- and 600 mg racemic ibuprofen.

The pharmacokinetic parameters in humans showed that S(+)-ibuprofen was not inverted to R(−)-ibuprofen, whereas R(−)-ibuprofen was inverted to S(+)-ibuprofen to a variable degree. S(+)-ibuprofen and R(−)-ibuprofen given alone more rapidly reached significantly higher maximal plasma concentrations than after the same doses of the racemic compound. The elimination half-lives and clearance values for all three forms of ibuprofen were comparable. The mean residence time of S(+)-ibuprofen after R(−)- and racemic ibuprofen was significantly longer than after administration of the pure S(+)-enantiomer.

Judged by the AUC, the bioavailability of S(+)-ibuprofen was independent of the dose within the range tested.

Administration of S(+)-ibuprofen to 6 rheumatic patients showed that the pharmacokinetic behaviour of S(+)-ibuprofen in patients was similar to that found in volunteers. S(+)-ibuprofen proved to be an effective analgesic antirheumatic drug in the dose range 1 to 1.5 g/day.

Key words

ibuprofen rheumatoid arthritis enantiomer stereoselectivity pharmacokinetics 

Preview

Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.

References

  1. 1.
    Jenner P, Testa B (1973) The influence of stereochemical factors on drug disposition. Drug Metabol Revs 2: 117–184Google Scholar
  2. 2.
    Ariens EJ (1986) Stereochemistry: A Source of Problems in Medicinal Chemistry. Med Res Revs 6, 4: 451–466Google Scholar
  3. 3.
    Ariens EJ, Wuis EW, Veringa EJ (1988) Stereoselectivity of Bioactive Xenobiotics. Biochem Pharmacol 37, 1: 9–18PubMedGoogle Scholar
  4. 4.
    Williams K, Lee E (1985) Importance of Drug Enantiomers in Clinical Pharmacology. Drugs 30: 333–354PubMedGoogle Scholar
  5. 5.
    Meffin PJ, Sallusto BC, Purdie YJ, Jones ME (1986) Enantioselective Disposition of 2-Arylpropionic Acid Nonsteroidal Anti-inflammatory Drugs. I. 2-Phenylpropionic Acid Disposition. J Pharmacol Exp Ther 238: 280–287PubMedGoogle Scholar
  6. 6.
    Hutt AJ, Caldwell J (1984) The importance of stereochemistry in the clinical pharmacokinetics of 2-arylpropionic acid non-steroidal anti-inflammatory drugs. Clin Phamacokinet 9: 371–373Google Scholar
  7. 7.
    Eichelbaum M, Mikus G, Vogelgesang B (1984) Pharmacokinetics of (+)-, (−)- and (±)-verapamil after intravenous administration. Br J Clin Pharmacol 17: 453–458PubMedGoogle Scholar
  8. 8.
    Adams SS, Bresloff P, Mason CG (1976) Pharmacological differences between the optical isomers of ibuprofen: evidence for metabolic inversion of the (−)-isomer. J Pharm Pharmacol 28: 256PubMedGoogle Scholar
  9. 9.
    Gaut ZN, Baruth H, Randall LO, Ashley C, Paulsrud JR (1975) Stereoisomeric relationships among anti-inflammatory activity, inhibition of platelet aggregation, and inhibition of prostaglandin synthetase. Prostaglandins 10: 59–66CrossRefPubMedGoogle Scholar
  10. 10.
    Kaiser DG, Vangiessen GJ, Reischer RJ, Wechter WJ (1976) Isomeric Inversion of Ibuprofen (R)-Enantiomer in Humans. J Pharm Sci 65, 2: 269–273PubMedGoogle Scholar
  11. 11.
    Lee EJD, Williams K, Day R, Graham G, Champion D (1985) Stereoselective disposition of ibuprofen enantiomers in man. Br J Clin Pharmacol 19: 669–674PubMedGoogle Scholar
  12. 12.
    Caldwell J, Hutt AJ, Fournel-Gigleux S (1988) The metabolic chiral inversion and dispositional enantioselectivity of the 2-arylpropionic acids and their biological consequences. Biochem Pharmacol 37, 1: 105–114CrossRefPubMedGoogle Scholar
  13. 13.
    Pitre D, Grandi M (1979) Rapid determination of ibuprofen in plasma by high performance liquid chromatography. J Chromatogr 170: 278–281PubMedGoogle Scholar
  14. 14.
    Lockwood GF, Wagner JG (1982) High performance liquid chromatographic determination of ibuprofen and its major metabolites in biological fluids. J Chromatogr 232: 335–343PubMedGoogle Scholar
  15. 15.
    Lockwood GF, Albert KS, Gillespie WR, Bole GG, Harcom TM, Szpunar J, Wagner JG (1983) Pharmacokinetics of ibuprofen in man. I. Free and total area/dose relationships. Clin Pharmacol Ther 34: 97–103PubMedGoogle Scholar
  16. 16.
    Albert KS, Gillespie WR, Wagner JG, Pau A, Lockwood GF (1984) Effects of age on the clinical pharmacokinetics of ibuprofen. Am J Med 77: 47–50PubMedGoogle Scholar
  17. 17.
    Janssen GME, Venema JF (1985) Ibuprofen: plasma concentrations in man. J Int Med Res 13: 68–75PubMedGoogle Scholar
  18. 18.
    Glass RC, Swannell AJ (1978) Concentrations of ibuprofen in serum and synovial fluid from patients with arthritis. Br J Clin Pharmacol 6: 453–454Google Scholar
  19. 19.
    Mäkelä AL, Lempiäinen M, Ylijoki H (1981) Ibuprofen levels in serum and synovial fluid. Scand J Rheumatol 39: 15–17Google Scholar
  20. 20.
    Jamali F, Singh NN, Pasutto FM, Russell AS, Coutts RT (1988) Pharmacokinetics of Ibuprofen Enantiomers in Humans Following Oral Administration of Tablets with Different Absorption Rates. Pharm Res 5: 40–43CrossRefPubMedGoogle Scholar
  21. 21.
    Lalande M, Wilson DL, McGilveray IJ (1986) Rapid high-performance liquid chromatographic determination of ibuprofen in human plasma. J Chromatogr 377: 413Google Scholar
  22. 22.
    Aarons L, Grennan DM, Rajapakse C, Brinkley J, Sidiqui M, Taylor L, Higham C (1983) Anti-inflammatory (ibuprofen) drug therapy in rheumatoid arthritis — rate of response and lack of time dependency of plasma pharmacokinetics. Br J Clin Pharmacol 15: 387–388PubMedGoogle Scholar
  23. 23.
    Ritchie DM, Boyle JA, McInnes JM, Jasani MR, Dalakos TG, Grieveson P, Buchmann WW (1968) Clinical studies with an articular index with the assessment of joint tenderness in patients with rheumatoid arthritis. Q J Med 37: 393–406PubMedGoogle Scholar
  24. 24.
    Deodhar SD, Dick WC, Hodgkinson R, Buchanan WW (1973) Measurement of clinical response to anti-inflammatory drug therapy in rheumatoid arthritis. Q J Med 42: 387–401PubMedGoogle Scholar
  25. 25.
    Geisslinger G, Dietzel K, Loew D, Schuster O, Rau G, Lachmann G, Brune K (1989) High-performance liquid chromatographic determination of ibuprofen, its metabolites and enantiomers in biological fluids. J Chromatogr 491: 139–149PubMedGoogle Scholar
  26. 26.
    Heinzel G (1982) Topfit. In: Bozler G, van Rossum JM (eds) Drug development and evaluation, vol 6. Fischer, Stuttgart, pp 207–208Google Scholar
  27. 27.
    Jamali F (1988) Pharmacokinetics of enantiomers of chiral nonsteroidal anti-inflammatory drugs. Eur J Drug Metabol Pharmacokinet 13, 1: 1–9Google Scholar
  28. 28.
    Nicholson JS, Tantum JG (1980) Preparation of Therapeutic Agents. United States Patent # 4209638: 3–8Google Scholar
  29. 29.
    Williams K, Day R, Knihinicki R, Duffield A (1986) The stereoselective uptake of ibuprofen enantiomers into adipose tissue. Biochem Pharmacol 35: 3403–3405PubMedGoogle Scholar
  30. 30.
    Aronson JK, Dengler HJ, Dettli L, Follath F (1988) Standardization of Symbols in Clinical Pharmacology. Eur J Clin Pharmacol 35: 1–7CrossRefPubMedGoogle Scholar

Copyright information

© Springer-Verlag 1990

Authors and Affiliations

  • G. Geisslinger
    • 1
  • O. Schuster
    • 2
  • K. -P. Stock
    • 3
  • D. Loew
    • 4
  • G. L. Bach
    • 3
  • K. Brune
    • 1
  1. 1.Department of Pharmacology and ToxicologyUniversity of ErlangenErlangenGermany
  2. 2.PAZ Arzneimittelentwicklungsgesellschaft mbHFrankfurt/MainGermany
  3. 3.Klinik HerzoghoeheBayreuthGermany
  4. 4.KaternbergerstraßeWuppertalGermany

Personalised recommendations