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Predictability of the clinical potency of NSAIDs from the preclinical pharmacodynamics in rats

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Abstract

Objective and Design: Relevance of the preclinical pharmacodynamic, toxicity and pharmacokinetic parameters predicting the clinical potency of nonsteroidal antiinflammatory drugs (NSAIDs) was evaluated.

Material: Data for oral potencies of 24 NSAIDs in rats were collected from the literature and from New Drug Applications with respect to the following parameters: antiinflammatory, analgesic, antipyretic, acute ulcerogenic activities, acute toxicity, in vitro inhibition of prostaglandin synthesis, acid dissociation constant (pKa), octanolwater partition coefficient and elimination half-life.

Treatment: Data for most of the in vivo parameters in rats were collected following single dose administration with the exception of adjuvant arthritis. Single and daily clinical doses were considered. All of these NSAIDs have been approved for marketing although not all have been sold in the USA.

Methods: The preclinical data were compared to human dose (unit or daily doses) using single and multiple stepwise regression analyses.

Results: Analyses suggest that NSAIDs are effective in all models of preclinical tests for fever, pain and inflammation, however, carrageenin-induced rat paw edema model is clearly the best predictor of human dose. Rank order of preclinical models for predicting human dose is carrageenin >yeast induced fever>pressure induced pain=adjuvant arthritis in rats. The analysis suggested that the pain and adjuvant arthritis models in rats may also involve a prostaglandin independent mechanism. Of the two physicochemical factors tested, pKa contributed best to the carrageenin model towards predicting the clinical potency of NSAIDs. Mathematical relationships between human dose, carrageenin ED50 and pKa were established that may assist in the future clinical development of NSAIDs.

Conclusions: Carrageenin-induced paw edema model in rats is the most robust predictor of the clinical potency of NSAIDs. Acid dissociation constant (pKa) appears to be a secondary contributor to the potency of NSAIDs. The relevance of the data analyses for developing cyclooxygenase-2 (COX-2) selective NSAIDs is discussed.

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References

  1. Martin BK. Significant factors in the history of aspirin. In: Dixon AJ, Smith MJH, Martin BK, Wood PHN, editors. Salicylates. London: J&A Churchill, 1963:6–8.

    Google Scholar 

  2. Smith MJH. Salicylates and metabolism. J Pharm Pharmacol 1959;11:705–20.

    CAS  PubMed  Google Scholar 

  3. Whitehouse MW. Properties of antiinflammatory drugs. In: Zucker E, editor. Progress in Drug Research. Vol 8. Basel: Birkhäuser, 1965:323–429.

    Google Scholar 

  4. Born GVR. Aggregation of blood platelets by adenosine diphosphate and its reversal. Nature 1962;194:927–9.

    CAS  PubMed  Google Scholar 

  5. Vane JR. Inhibition of prostaglandin synthesis as a mechanism of action of aspirin like drugs. Nature New Biol 1971;231:232–5.

    CAS  PubMed  Google Scholar 

  6. Day RO, Graham GG, Williams KM, Champion GD, Jager JD. Clinical pharmacology of NSAIDs. In: Orme MC, editor. Anti-rheumatic drugs. New York: Pergamon Press, 1990:137–87.

    Google Scholar 

  7. Furst DE. Are there differences among nonsteroidal antiinflammatory drugs. Arthr Rheum 1994;37:1–9.

    CAS  Google Scholar 

  8. Brune K, Beck WS, Geisslinger G, Menzel-Soglowek S, Peskar BM. Aspirin-like drugs may block pain independently of prostaglandin synthesis inhibition. Experientia 1991;47:257–61.

    Article  CAS  PubMed  Google Scholar 

  9. Adams SS, McCullough KF, Nicholson JS. Some biological properties of flurbiprofen, an anti-inflammatory, analgesic and antipyretic agent. Drug Res 1975;25:1786–91.

    CAS  Google Scholar 

  10. Brogden RN, Heel RC, Speight TM, Avery GS. Fenbufen: A review of its pharmacological properties and therapeutic use in rheumatic diseases and acute pain. Drugs 1981;21:1–22.

    CAS  PubMed  Google Scholar 

  11. Brooks RR, Bonk KR, Decker GE, Miller KE. Anti-inflammatory activity of orpanoxin administered orally and topically to rodents. Agents Actions 1985;16:369–76.

    Article  CAS  PubMed  Google Scholar 

  12. Burns JJ, Yu TF, Dayton PG, Gutman AB, Brodie BB. Biochemical pharmacological considerations of phenylbutazone and its analogues. Ann NY Acad Sci 1960;86:253–62.

    CAS  PubMed  Google Scholar 

  13. Capetola RJ, Shriver DA, Rosenthale ME. Suprofen, a new peripheral analgesic. J Pharmac Exp Ther 1980;214:16–23.

    CAS  Google Scholar 

  14. Capetola RJ, Tolman EL, Argentieri DC, Simon DM, Rosenthal ME. Suprofen. In: Lewis AJ, Furst DE, editors. Nonsteroidal anti-inflammatory drugs. New York: Marcel Dekker, 1987:509–30.

    Google Scholar 

  15. Carty TJ, Eskra JD, Lombardino JG, Hoffman WW. Piroxicam, a potent inhibitor of prostaglandin production in cell culture. Structure-activity study. Prostaglandins 1980;19:51–9.

    CAS  PubMed  Google Scholar 

  16. Chipkin RE, Latranyi MB, Lorio LC, Barnett A. Determination of analgesic drug efficacies by modification of the Randall and Selitto Rat Yeast Paw test. J Pharmacol Meth 1983;10: 223–9.

    Article  CAS  Google Scholar 

  17. Davies RO. Review of the animal and clinical pharmacology of diflunisal. Pharmacotherapy 1983;3 Suppl:9S-22.

    CAS  PubMed  Google Scholar 

  18. Demerson CA, Humber LG, Abraham NA, Schilling G, Martel RR, Pace-Asciak C. Resolution of etodolac and anti-inflammatory and prostaglandin synthetase inhibiting properties of the enantiomers. J Med Chem 1983;26:1778–80.

    Article  CAS  PubMed  Google Scholar 

  19. Egg D. Effects of glycosaminoglycan-polysulfate and two nonsteroidal anti-inflammatory drugs on prostaglandin E2 synthesis in chinese hamster ovary cell cultures. Pharmacol Res Commun 1983;15:709–17.

    CAS  PubMed  Google Scholar 

  20. Enthoven D, Coffey JW, Wyler-Plaut. Carprofen. In: Lewis AJ, Furst DE, editors. Nonsteroidal anti-inflammatory drugs. New York: Marcel Dekker, 1987:313–28.

    Google Scholar 

  21. Erikson N, Furst DE. Mechanisms of action of nonsteroidal anti-inflammatory drugs. Am Ass Clin Chem 1988;9:9–18.

    Google Scholar 

  22. Eve NO. Tiaprofenic acid. In: Lewis AJ, Furst DE, editors. Nonsteroidal anti-inflammatory drugs. New York: Marcel Dekker, 1987:531–46.

    Google Scholar 

  23. Ferrari RA, Ward SJ, Zobre CM, Van Liew DK, Perrone MH, Connell MJ, et al. Estimation of the in vivo effect of cyclooxygenase inhibitors on prostaglandin E2 levels in mouse brain. Eur J Pharmacol 1990;179:25–34.

    Article  CAS  PubMed  Google Scholar 

  24. Goldenberg MM, Boise KL, Ilse AC, Evaluation of a new anti-inflammatory/analgesic compound F-776, 5-(4-chlorophenyl)-β-hydroxy-2-furanpropanoic acid. Arch Int Pharmacodyn 1980;243:331–51.

    CAS  PubMed  Google Scholar 

  25. Goto J, Muramatsu M, Hosoda K, Otomo S, Aihara H. The inhibitory effect of oxaprozin, a new non-steroidal anti-inflammatory drug on platelet aggregation. Folia Pharmacol Jpn 1984:83:395–400.

    CAS  Google Scholar 

  26. Grindel JM, O'Neill PJ, Yorgey KA, Schwartz MH, McKown LA, Migdalof BH, et al. The metabolism of zomepirac sodium. I. Disposition in laboratory animals and man. Drug Metab Dispos Biol Fate Chem 1980;8:343–8.

    CAS  PubMed  Google Scholar 

  27. Guissou P, Cuisinaud G, Legheand J, Sassard J. Chronopharmacokinetics of indomethacin in rats. Drug Res 1987;37: 1034–7.

    CAS  Google Scholar 

  28. Hatanaka T, Inuma M, Sugibayashi K, Morimoto Y. Prediction of skin permeability of drugs. I. Comparison with artificial membrane. Chem Pharm Bull 1990;38:3452–9.

    CAS  PubMed  Google Scholar 

  29. Herzfeldt CD, Kummel R. Dissociation constants, solubilities and dissolution rates of some selected nonsteroidal anti-inflammatories. Drug Development and Industrial Pharmacy 1983;9:767–93.

    CAS  Google Scholar 

  30. Higuchi S, Osada Y, Shioiri Y, Nakaike S, Muramatsu M, Tanaka M, et al. Anti-inflammatory activity of a non-steroidal anti-inflammatory agent, oxaprozin, in experimental animal models. Folia Pharmacol Jpn 1984;83:383–94.

    CAS  Google Scholar 

  31. Krause W, Kuhne G, Schillinger E. Pharmacokinetics and biotransformation of methane sulphonanilides with anti-inflammatory activity in the rat and monkey-comparison with piroxicam. Xenobiotica 1983;13:265–72.

    CAS  PubMed  Google Scholar 

  32. Kuriyama K, Hiyama Y, Aoyama Y, Ichikawa K, Okumura M, Masumoto S, et al. Pharmacological studies of a non-steroidal analgesic and antipyretic drug of LFP 83. Folia Pharmacol Jpn 1989;93:61–73.

    CAS  Google Scholar 

  33. La-Rotanda MI, Cappelo B, Grimaldi M, Silipo C, Vittoria A. Analysis of the correlation between hydrophilic-lipophilic series of nonsteroidal anti-inflammatory drugs. Farmaco Sci 1988;43:439–55.

    Google Scholar 

  34. Laneuville O, Breuer DK, Dewitt DL, Hla T, Funk CD, Smith WL. Differential inhibition of human prostaglandin endoperoxide H synthases-1 and-2 by nonsteroidal antiinflammatory drugs. J Pharmac Exp Ther 1994;271:927–34.

    CAS  Google Scholar 

  35. Levesque L, Gaudreault RC, Marceau F. The interaction of 3,5-pyrazolidienedione drugs with receptors for f-Met-Leu-Phe on human neutrophil leukocytes: a study of their structure-activity relationship. Can J Physiol Pharmacol 1991;69:419–25.

    CAS  PubMed  Google Scholar 

  36. Liauw L, Moscaritola JD, Burcher J. Diclofenac. In: Lewis AJ, Furst DE, editors. Nonsteroidal anti-inflammatory drugs. New York: Marcel Dekker, 1987:329–47.

    Google Scholar 

  37. Lombardino JG. Medicinal chemistry of acidic nonsteroidal antiinflammatory drugs. In: Lombardino JG, editor. Nonsteroidal antiinflammatory drugs. New York: John Wiley, 1985:266–397.

    Google Scholar 

  38. Lombardino JG, Otterness IG, Wiseman EH. Acidic anti-inflammatory agents, pharmacological and clinical data. Drug Res 1975;25:1629–35.

    CAS  Google Scholar 

  39. Loscher W, Blazaki D. Effect of non-steroidal anti-inflammatory drugs on fertility of male rats. J Reprod Fertil 1986;76:65–73.

    CAS  PubMed  Google Scholar 

  40. Majerus PW, Stanford N. Comparative effects of aspirin and diflunisal on prostaglandin synthetase from human platelets and sheep seminal vesicles. J Clin Pharmac 1977;4 Suppl:15S-8.

    Google Scholar 

  41. Mangan FR. Nabumetone. In: Lewis AJ, Furst DE, editors. Nonsteroidal anti-inflammatory drugs. New York: Marcel Dekker, 1987:439–72.

    Google Scholar 

  42. Marshall L, Dietrich S, Chang J. Anti-inflammatory drug effects on arachidonic acid metabolism in glycogen-elicited rat peritoneal cells as determined by a one-step chromatographic procedure. Ann NY Acad Sci 1988;524:442–4.

    Google Scholar 

  43. Martel RR, Klicius J. Comparison in rats of the anti-inflammatory and gastric irritant effects of etodolac with several clinically effective anti-inflammatory drugs. Agents Actions 1982;12:295–7.

    Article  CAS  PubMed  Google Scholar 

  44. Menasse R, Hedwall PR, Kraetz J, Pericin C, Riesterer L, Sallmann A, et al. Pharmacological properties of diclofenac sodium and its metabolites. Scand J Rheumatol 1978;22 Suppl:5s-16.

    Google Scholar 

  45. Berkow R, editor. Merck Manual of diagnosis and therapy. Rahway, N.J. Merck Research Laboratories, 1992.

    Google Scholar 

  46. Muchowski JM, Unger SH, Ackrell J, Cooper GF, Cook J, Gallegra P, et al. Synthesis and antiinflammatory and analgesic activity of 5-Aroyl-1,2-dihydro-3H-pyrrolo[1,2-a′]pyrole-1-carboxylic acids and related compounds. J Med Chem 1985; 28:1037–49.

    Article  CAS  PubMed  Google Scholar 

  47. Nagatomi H, Ando K. Studies on the anti-inflammatory activity and ulcerogenic adverse effect of thiazole derivatives, especially 2-amino-thiazoleacetic acid derivatives. Drug Res 1984;43:599–603.

    Google Scholar 

  48. Otterness IG, Gans DJ. Nonsteroidal anti-inflammatory drugs: an analysis of the relationship between laboratory animal and clinical doses. J Pharm Sci 1988;77:790–5.

    CAS  PubMed  Google Scholar 

  49. Palmer DG, Highton J, Mackinnon, Myers DB. Non-steroidal anti-inflammatory drugs in combination. Experimental observations. Clin Exp Rheum 1985;3:111–5.

    CAS  Google Scholar 

  50. Pong SF, Demuth SM, Kinney CM, Deegan P. Prediction of human analgesic dosages of nonsteroidal anti-inflammatory drugs from analgesic ED50 values in mice. Arch Int Pharmacodyn 1985;273:212–20.

    CAS  PubMed  Google Scholar 

  51. Rainsford KD, editor. Salicylates. In: Anti-inflammatory and anti-rheumatic drugs. Florida: CRC Press, 1985:112.

    Google Scholar 

  52. Randall LO, Baruth H. Analgesic and anti-inflammatory activity of 6-chloro-alpha-methyl-carbazole-2-acetic acid. Arch Int Pharmacodyn 1976;220:94–114.

    CAS  PubMed  Google Scholar 

  53. Rechenberg HK. Phenylbutazone. London: Edward and Arnold, 1962:11–62.

    Google Scholar 

  54. Risdall PC, Adams SS, Crampton EL, Marchant B. The disposition and metabolism of flurbiprofen in several species including man. Xenobiotica 1978;8:691–704.

    CAS  PubMed  Google Scholar 

  55. Roszkowski AP, Rooks WH II, Tomolonis AJ, Miller LM. Anti-inflammatory properties of d-2-(6′-methoxy-2′ naphthyl)-propionic acid (naproxen). J Pharmac Exp Ther 1971;179:114–23.

    CAS  Google Scholar 

  56. Ruelius HW. Extrapolation from animals to man: Predictions, pitfalls and perspectives. Xenobiotica 1987;17:255–65.

    CAS  PubMed  Google Scholar 

  57. Said SA, Foda AM. Influence of cimetidine on the pharmacokinetics of piroxicam in rat and man. Drug Res 1989;39:790–2.

    CAS  Google Scholar 

  58. Sallmann A. The chemistry of diclofenac sodium. Rheumatol Rehabil 1979;18:4–10.

    Google Scholar 

  59. Sanda M, Jacob GB, Fliedner L, Kennedy J, Gotz M. Etodolac. In: Lewis AJ, Furst DE. editors. Nonsteroidal antiinflammatory drugs. New York: Marcel Dekker, 1987:349–70.

    Google Scholar 

  60. Satterwhite JH, Boudinot FD. Pharmacokinetics of ketoprofen in rats: effect of age and dose. Biopharm Drug Dis 1992;13:197–212.

    CAS  Google Scholar 

  61. Schiantarelli P, Cadel S. Piroxicam pharmacologic activity and gastrointestinal damage by oral and rectal route. Drug Res 1981;31:87–92.

    CAS  Google Scholar 

  62. Schuster T, Afeche P, Feldmann K. Phenylbutazone and oxyphenbutazone. In: Rainsford KD, editor. Antiinflammatory and antirheumatic drugs. Florida: CRC Press, 1985:161–74.

    Google Scholar 

  63. Shen TV. Chemical and pharmacological properties of diflunisal. Pharmacotherapy 1983;3 Suppl 2:3S-8.

    CAS  PubMed  Google Scholar 

  64. Sloboda AE, Oronsky AL, Kerwar SS. Fenbufen. In: Lewis AJ, Furst DE, editors. Nonsteroidal anti-inflammatory drugs. New York: Marcel Dekker, 1987:371–92.

    Google Scholar 

  65. Sloboda AE, Tolman EL, Osterberg AC, Panagides J. The pharmacological properties of fenbufen. Drug Res 1980;30: 716–21.

    CAS  Google Scholar 

  66. Smith RJ, Lomen PL, Kaiser DG. Flurbiprofen. In: Lewis AJ, Furst DE, editors. Nonsteroidal anti-inflammatory drugs. New York: Marcel Dekker, 1987:393–418.

    Google Scholar 

  67. Tarayre JP, Lauressergues H. Advantages of a combination of proteolytic enzymes, flavonoids and ascorbic acid in comparison with non-steroid anti-inflammatory agents. Drug Res 1977;27:1144–9.

    CAS  Google Scholar 

  68. Varma DR. Influence of dietary protein on the anti-inflammatory and ulcerogenic effects and on the pharmacokinetics of phenylbutazone in rats. J Pharmac Exp Ther 1979;211:338–44.

    CAS  Google Scholar 

  69. Wax J, Winder CV, Tessman DK, Stephens MD. Comparative activities, tolerance and safety of nonsteroidal anti-inflammatory agents in rats. J Pharmac Exp Ther 1975;192: 172–8.

    CAS  Google Scholar 

  70. Wiseman EH, Chang YH, Lombardino JG. Piroxicam, a novel anti-inflammatory agent. Drug Res 1976;26:1300–3.

    CAS  Google Scholar 

  71. Plakogiannis FM, McCauley JA. Sulindac. In: Florey K, editor. Analytical profiles of substances. New York: Academic Press, 1984:584.

    Google Scholar 

  72. Mihalic M, Hofman H, Kuftinec J, Krile B, Caplar V, Kajfez F, et al. Piroxicam. In: Florey K, editor. Analytical profiles of substances. New York: Academic Press, 1986;15:524.

    Google Scholar 

  73. Winter CA, Risely EA, Nuss CW. Carrageenin induced edema in hind paw of the rat as an assay for antiinflammatory drugs. Proc Soc Exp Biol Med 1962;111:544–7.

    CAS  PubMed  Google Scholar 

  74. Newbould BB. Chemotherapy of arthritis induced in rats by mycobacterial adjuvant. Br J Pharmacol 1963;21:127–36.

    CAS  Google Scholar 

  75. Randall LO, Selitto JJ. A method for measurement of analgesic activity of inflamed tissue. Arch Int Pharmacodyn 1957;111:409–19.

    CAS  PubMed  Google Scholar 

  76. Winder CV, Wax J, Serrano B, Scotti L, Stackhouse SP, Wheelock RH. Pharmacological studies of 1,2-dimethyl-3-phenyl-3-propionoxy pyrolidine, CI-427, an analgesic agent. J Pharmac Exp Ther 1961;133:117–28.

    CAS  Google Scholar 

  77. Dodge PW, Brodie DA, Young PR, Krause RA, Tekeli S. Presentation of antiinflammatory drug induced gastric lesions in rats by Abbott-29590. Am J Dig Dis 1974;19:449–57.

    Article  CAS  PubMed  Google Scholar 

  78. Litchfield JT, Wilcoxon F. A simplified method of evaluating dose-effect experiments. J Pharmac Exp Ther 1949;96:99–113.

    CAS  Google Scholar 

  79. Otterness IG, Wiseman EH, Gans DJ. A comparison of the carrageenin edema test and ultraviolet light induced erythema test as predictors of the clinical dose in rheumatoid arthritis. Agents Actions 1979;9:177–83.

    CAS  PubMed  Google Scholar 

  80. Furst DE, Paulus HE. Aspirin and other NSAIDs. In: McCarty DJ, Koopman WJ, editors. Arthritis and allied conditions. Vol 1. Philadelphia: Lea and Febiger, 1993: 567–602.

    Google Scholar 

  81. Cricket Software, Malvern PA, Cricket Graph v 1.3 for Macintosh, 1988.

  82. Cox DR, Snell EJ, editors. Applied Statistics. New York, London: Chapman and Hall, 1982;20–42.

    Google Scholar 

  83. JMP Statistics and Graphics Guide. Version 3.1, SAS Institute, Cary, NC.

  84. Johnson AG, Siedmann P, Day RO. NSAID-related adverse drug interactions with clinical relevance. Int J Clin PHarm Ther 1994;32:509–32.

    CAS  Google Scholar 

  85. Katz LM, Love PY. NSAIDs and the liver. In: Famaey JP, Paulus HE, editors. Therapeutic applications of NSAIDs. New York: Marcel Dekker, 1992:247–63.

    Google Scholar 

  86. Brooks PM, Day RO. Nonsteroidal antiinflammatory drugs, differences and similarities. New Engl J Med 1991;324:1716–25.

    CAS  PubMed  Google Scholar 

  87. Brune K, Graf P, Glatt M. Inhibition of prostaglandin synthesis in vivo by nonsteroid anti-inflammatory drugs. Evidence for the importance of pharmacokinetics. Agents Actions 1976; 6:159–64.

    Article  CAS  PubMed  Google Scholar 

  88. Futaki N, Takahashi S, Yokoyama N, Arai I, Higuchi S, Otomo S. NS-398, a new antiinflammatory agent, selectively inhibits prostaglandin G/H synthase/cyclooxygenase (COX-2) activity in vitro. Prostaglandins 1994;47:55–9.

    Article  CAS  PubMed  Google Scholar 

  89. Chan CC, Boyce S, Brideau C, Ford-Hutchinson AW, Gordon R, Guay D, et al. Pharmacology of a selective cyclooxygenase-2 inhibitor, L-745,337: A novel nonsteroidal anti-inflammatory agent with an ulcerogenic sparing effect in rat and nonhuman primate stomach. J Pharmac Exp Ther 1995;274:1531–7.

    CAS  Google Scholar 

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Author notes

  1. V. G. Hale

    Present address: Genentech Inc., MS-70, 94080, South San Francisco, CA, USA

  2. O. Borga

    Present address: Astra Draco AB, P.O. Box 34, S-221 00, Lund, Sweden

Authors and Affiliations

  1. Division of Anti-inflammatory, Analgesic and Ophthalmologic Drug Products, 5600 Fishers Lane, 20857, Rockville, MD, USA

    A. Mukherjee & R. Stein

  2. Office of Clinical Pharmacology and Biopharmaceutics, Center for Drug Evaluation and Research, Food and Drug Administration (FDA), 5600 Fishers Lane, 20857, Rockville, MD, USA

    V. G. Hale & O. Borga

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Mukherjee, A., Hale, V.G., Borga, O. et al. Predictability of the clinical potency of NSAIDs from the preclinical pharmacodynamics in rats. Inflamm Res 45, 531–540 (1996). https://doi.org/10.1007/BF02342223

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