Skip to main content
SpringerLink
Log in

Chirality and Nonsteroidal Anti-Inflammatory Drugs

  • Published:
Drugs Aims and scope Submit manuscript

Summary

The nonsteroidal anti-inflammatory drugs (NSAIDs) are of significant clinical importance and include congeners of many chemical classes, some of which incorporate an asymmetric or chiral carbon atom. With very few exceptions, chiral NSAIDs have been marketed for clinical use as racemates. However, it is apparent that differences, sometimes major, exist between enantiomers in terms of their pharmacological and toxicological properties. With regard to the ability of chiral NSAIDs to inhibit cyclo-oxygenase, their chief mechanism of action, major or exclusive activity is confined to enantiomers of the S-stereoconfiguration. Accordingly, it is questionable whether the R-antipodes should be included in the final drug product for use in the clinic. In addition to differences between enantiomers in terms of their pharmacodynamic properties, pharmacokinetic differences are possible for chiral NSAID isomers, and these may modulate preexisting enantioselectivities at the site of action of such compounds. As a consequence, a considerably simpler pharmacological profile is likely to result from the use of single enantiomers versus racemic mixtures.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

References

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

    CAS  Google Scholar 

  2. Takeguchi C, Sih CJ. A rapid spectrophotometric assay for prostaglandin synthetase: application to the study of non-steroidal anti-inflammatory agents. Prostaglandins 1972; 2: 169–84

    Article  PubMed  CAS  Google Scholar 

  3. Lewis AJ, Furst DE. Non-steroidal anti-inflammatory drugs: mechanisms and clinical uses. 2nd ed. New York: Marcel Dekker, 1994: 1–2

    Google Scholar 

  4. Vane JR, Botting RM. The mode of action of anti-inflammatory drugs. Postgrad Med J 1990; 66 Suppl. 4: S2–17

    PubMed  CAS  Google Scholar 

  5. Cashman J, McAnulty G. Nonsteroidal anti-inflammatory drugs in perisurgical pain management. Drugs 1995; 49: 51–70

    Article  PubMed  CAS  Google Scholar 

  6. Evans AM. Enantioselective pharmacodynamics and pharma-cokinetics of chiral non-steroidal anti-inflammatory drugs. Eur J Clin Pharmacol 1992; 42: 237–56

    Article  PubMed  CAS  Google Scholar 

  7. Hutt AJ, Caldwell J. The metabolic chiral inversion of 2-arylpropionic acids — a novel route with pharmacological consequences. J Pharm Pharmacol 1983; 35: 693–704

    Article  PubMed  CAS  Google Scholar 

  8. Williams KM. Enantiomers in arthritic disorders. Pharmacol Ther 1990; 46: 273–95

    Article  PubMed  CAS  Google Scholar 

  9. Gaut ZN, Baruth H, Randall LO, et al. Stereoisomeric relationships among anti-inflammatory activity, inhibition of platelet aggregation, and inhibition of prostaglandin synthetase. Prostaglandins 1975; 10: 59–66

    PubMed  CAS  Google Scholar 

  10. Rubin A, Knadler MP, Ho PPK, et al. Stereoselective inversion of (R)-fenoprofen to (S)-fenoprofen in humans. J Pharm Sci 1985; 74: 82–4

    Article  PubMed  CAS  Google Scholar 

  11. Evans AM, Nation RL, Sansom LN, et al. Effect of racemic ibuprofen dose on the magnitude and duration of platelet cyclo-oxygenase inhibition: relationship between inhibition of thromboxane production and the plasma unbound con-centration of S(+)-ibuprofen. Br J Clin Pharmacol 1991; 31: 131–8

    Article  PubMed  CAS  Google Scholar 

  12. Cerletti C, Manarini S, Colombo M, et al. The (+)-enantiomer is responsible for the antiplatelet and anti-inflammatory activity of (±)-indobufen. J Pharm Pharmacol 1990; 42: 885–7

    Article  PubMed  CAS  Google Scholar 

  13. Hayball PJ, Nation RL, Bochner F. Enantioselective pharmacodynamics of the nonsteroidal antiinflammatory drug ketoprofen: in vitro inhibition of human platelet cyclo-oxygenase activity. Chirality 1992; 4: 484–7

    Article  PubMed  CAS  Google Scholar 

  14. Suesa N, Fernandez MR, Gutierrez M, et al. Stereoselective cyclooxygenase inhibition in cellular models by the enantiomers of ketoprofen. Chirality 1993; 5: 589–95

    Article  PubMed  CAS  Google Scholar 

  15. Williams KM. Chiral NSAIDs: so what? Agents Actions Suppl 1993; 44: 15–22

    PubMed  CAS  Google Scholar 

  16. Hayball PJ, Nation RL, Bochner F, et al. The influence of renal function on the enantioselective pharmacokinetics and pharmacodynamics of ketoprofen in patients with rheumatoid arthritis. Br J Clin Pharmacol 1993; 36: 185–93

    Article  PubMed  CAS  Google Scholar 

  17. Vane JR. Towards a better aspirin. Nature 1994; 367: 215–6

    Article  PubMed  CAS  Google Scholar 

  18. Dray A, Bevan S. Inflammation and hyperalgesia: the team effort. Trends Pharm Sci 1993; 14: 287–90

    Article  PubMed  CAS  Google Scholar 

  19. Aslanian R, Carruthers NI, Kaminski JJ. Cyclo-oxygenase-2: a novel target for therapeutic intervention. Exp Opin Invest Drugs 1994; 3: 1323–5

    Article  Google Scholar 

  20. Hayllar J, Bjarnason I. NSAIDs, COX-2 inhibitors, and the gut. Lancet 1995; 346: 521–2

    Article  PubMed  CAS  Google Scholar 

  21. Somasundaram S, Hayllar H, Rafi S, et al. The biochemical basis of non-steroidal anti-inflammatory drug-induced damage to the gastrointestinal tract: a review and a hypothesis. Scand J Gastroenterol 1995; 30: 289–99

    Article  PubMed  CAS  Google Scholar 

  22. Meade EA, Smith WL, DeWitt DL. Differential inhibition of prostaglandin endoperoxide synthase (cyclooxygenase) isozymes by aspirin and other nonsteroidal anti-inflammatory drugs. J Biol Chem 1993; 268: 6610–14

    PubMed  CAS  Google Scholar 

  23. Cipollone F, Ganci A, Panara MR, et al. Effects of nabumetone on prostanoid biosynthesis in humans. Clin Pharmacol Ther 1995; 58: 335–41

    Article  PubMed  CAS  Google Scholar 

  24. Patrignani P, Panara MR, Greco A, et al. Biochemical and pharmacological characterization of the cyclooxygenase activity of human blood prostaglandin endoperoxide synthases. J Pharmacol Exp Ther 1994; 271: 1705–12

    PubMed  CAS  Google Scholar 

  25. Panara MR, Greco A, Santini G, et al. Effects of the novel anti-inflammatory compounds, N-[2-(cyclohexyloxy)-4-nitrophenyl] methanesuphonamide (NS-398) and 5-methane-sulphonamido-6-(2,4-difluorothiophenyl)-l-indanone (L-745,337), on the cyclo-oxygenase activity of human blood prostaglandin endoperoxide synthases. Br J Pharmacol 1995; 116: 2429–34

    Article  PubMed  CAS  Google Scholar 

  26. Matsuda K, Tanaka Y, Ushiyama S, et al. Inhibition of prostaglandin synthesis by sodium 2-[4-(2-oxocyclopentylmethyl) phenyl]-propionate dihydrate (CS-600), a new anti-inflammatory drug, and its active metabolite in vitro and in vivo. Biochem Pharmacol 1984; 15: 2473–8

    Article  Google Scholar 

  27. Ferreira SH, Vane JR. Mode of action of anti-inflammatory agents which are prostaglandin synthetase inhibitors. In: Vane JR, Ferreira SH, editors. Anti-inflammatory drugs. Berlin: Springer, 1979

    Google Scholar 

  28. Tomlinson RV, Ringold HJ, Qureshi MC, et al. Relationship between inhibition of prostaglandin synthesis and drug efficacy: support for the current theory on mode of action of aspirin-like drugs. Biochem Biophys Res Commun 1972; 46: 552–8

    Article  PubMed  CAS  Google Scholar 

  29. Abramson SB, Weissmann G. The mechanism of action of nonsteroidal antiinflammatory drugs. Arthritis Rheum 1989; 32: 1–9

    Article  PubMed  CAS  Google Scholar 

  30. Day RO, Graham GG, Williams KM, et al. Clinical pharmacology of non-steroidal anti-inflammatory drugs. Pharmacol Ther 1987; 33: 383–433

    Article  PubMed  CAS  Google Scholar 

  31. Goodwin JS. Mechanism of action of nonsteroidal anti-inflammatory drugs. Am J Med 1984; 77 Suppl. 1A: 57–64

    Article  PubMed  CAS  Google Scholar 

  32. Brune K, Beck WS, Geisslinger G, et al. Aspirin-like drugs may block pain independently of prostaglandin synthesis inhibition. Experientia 1991; 47: 257–60

    Article  PubMed  CAS  Google Scholar 

  33. Brune K, Rainsford KD, Wagner K, et al. Inhibition by anti-inflammatory drugs of prostaglandin production in cultured macrophages. Factors influencing the apparent drug effects. Naunyn-Schmiedebergs Arch Pharmacol 1981; 315: 269–76

    Article  PubMed  CAS  Google Scholar 

  34. Rosenkranz B, Fisher C, Meese CO, et al. Effects of salicylic and acetylsalicylic acid alone and in combination on platelet aggregation and prostanoid synthesis in man. Br J Clin Pharmacol 1986; 21: 309–17

    Article  PubMed  CAS  Google Scholar 

  35. Brandt KD, Palmoski MJ. Effects of salicylates and other non-steroidal anti-inflammatory drugs on articular cartilage. Am J Med 1984; 77 Suppl. 1A: 65–9

    Article  PubMed  CAS  Google Scholar 

  36. Shelly J, Hoff SF. Effects of non-steroidal anti-inflammatory drugs on isolated human polymorphonuclear leukocytes (PMN): chemotaxis, Superoxide production, degranulation and N-formyl-L-methionyl-L-leucyl-L-phenylalanine (fMLP) receptor binding. Gen Pharmacol 1989; 20: 329–34

    Article  PubMed  CAS  Google Scholar 

  37. Rampart M, Williams TJ. Suppression of inflammatory oedema by ibuprofen involving a mechanism independent of cyclo-oxygenase inhibition. Biochem Pharmacol 1986; 35: 581–6

    Article  PubMed  CAS  Google Scholar 

  38. Freneaux E, Fromenty B, Berson A, et al. Stereoselective and nonstereoselective effects of ibuprofen enantiomers on mitochondrial β-oxidation of fatty acids. J Pharmacol Exp Ther 1990; 255: 529–35

    PubMed  CAS  Google Scholar 

  39. Geneve J, Hayat-Bonan B, Labbe G, et al. Inhibition of mitochondrial β-oxidation of fatty acids by pirprofen. Role in microvesicular steatosis due to this nonsteroidal anti-inflammatory drug. J Pharmacol Exp Ther 1987; 242: 1133–7

    PubMed  CAS  Google Scholar 

  40. Zhao B, Geisslinger G, Hall I, et al. The effect of the enantiomers of ibuprofen and flurbiprofen on the β-oxidation of palmitate in the rat. Chirality 1992; 4: 137–41

    Article  PubMed  CAS  Google Scholar 

  41. Twomey BM, Dale MM. Cyclooxygenase-independent effects of non-steroidal anti-inflammatory drugs on the neutrophil respiratory burst. Biochem Pharmacol 1992; 43: 413–8

    Article  PubMed  CAS  Google Scholar 

  42. Kawai K, Shiojiri H, Fukushima H, et al. The effect of clindanac, a potent anti-inflammatory drug, on mitochondrial respiration: a consideration of the uncoupling activity of optical enantiomers. Res Commun Chem Pathol Pharmacol 1984; 45: 399–406

    PubMed  CAS  Google Scholar 

  43. Villanueva M, Heckenberger R, Strobach H, et al. Equipotent inhibition by R(−)-ibuprofen, S(+)-ibuprofen and racemic ibuprofen of human polymorphonuclear cell function in vitro. Br J Clin Pharmacol 1993; 35: 235–42

    Article  PubMed  CAS  Google Scholar 

  44. Jamali F, Mehvar R, Pasutto FM. Enantioselective aspects of drug action and disposition: therapeutic pitfalls. J Pharm Sci 1989; 78: 695–715

    Article  PubMed  CAS  Google Scholar 

  45. Lee EJD, Williams KM. Chirality: clinical pharmacokinetic and pharmacodynamic considerations. Clin Pharmacokinet 1990; 18: 339–45

    Article  PubMed  CAS  Google Scholar 

  46. Tucker GT, Lennard MS. Enantiomer specific pharmacokinetics. Pharmacol Ther 1990; 45: 309–29

    Article  PubMed  CAS  Google Scholar 

  47. Ariens EJ. Stereochemistry, a basis for sophisticated nonsense in pharmacokinetics and clinical pharmacology. Eur J Clin Pharmacol 1984; 26: 663–8

    Article  PubMed  CAS  Google Scholar 

  48. Evans AM, Nation RL, Sansom LN, et al. Stereoselective drug disposition: potential for misinterpretation of drug disposition data. Br J Clin Pharmacol 1988; 26: 771–80

    Article  PubMed  CAS  Google Scholar 

  49. Jamali F, Mehvar R, Lemko C, et al. Application of a stereospecific high-performance liquid Chromatographic assay to a pharmacokinetic study of etodolac enantiomers in humans. J Pharm Sci 1988; 77: 963–6

    Article  PubMed  CAS  Google Scholar 

  50. Hayball PJ, Wrobel J, Tamblyn JG, et al. The pharmacokinetics of ketorolac enantiomers following intramuscular administration of the racemate. Br J Clin Pharmacol 1994; 37: 75–8

    Article  PubMed  CAS  Google Scholar 

  51. Guzman A, Yuste F, Toscano RA, et al. Absolute configuration of (−)-5-benzoyl-1,2-dihydro-3 H-pyrrolo[ 1,2α]pyrrole-1-carboxylic acid. J Med Chem 1986; 29: 589–91

    Article  PubMed  CAS  Google Scholar 

  52. Caldwell J, Winter SM, Hutt AJ. The pharmacological and toxi-cological significance of the stereochemistry of drug disposition. Xenobiotica 1988; 18 Suppl. 1: 59–70

    PubMed  CAS  Google Scholar 

  53. Eichelbaum M. Pharmacokinetic and pharmacodynamic consequences of stereoselective drug metabolism in man. Biochem Pharmacol 1988; 37: 93–6

    Article  PubMed  CAS  Google Scholar 

  54. Testa B. Substrate and product stereoselectivity in mono-oxygenase-mediated drug activation and inactivation. Biochem Pharmacol 1988; 37: 85–92

    Article  PubMed  CAS  Google Scholar 

  55. Evans AM, Nation RL, Sansom LN, et al. Stereoselective plasma protein binding of ibuprofen enantiomers. Eur J Clin Pharmacol 1989; 36: 283–90

    Article  PubMed  CAS  Google Scholar 

  56. Hayball PJ, Holman JW, Nation RL, et al. Marked enantioselective protein binding of ketorolac in vitro: elucidation of enantiomer unbound fractions following facile synthesis and direct chiral HPLC resolution of tritium-labelled ketorolac. Chirality 1994; 6: 642–8

    Article  PubMed  CAS  Google Scholar 

  57. Jamali F, Russell AS, Foster RT, et al. Ketoprofen pharmacokinetics in humans: evidence of enantiomeric inversion and lack of interaction. J Pharm Sci 1990; 79: 460–1

    Article  PubMed  CAS  Google Scholar 

  58. Caldwell J. Stereochemical determinants of the nature and consequences of drug metabolism. J Chromatogr A 1995; 694: 39–48

    Article  PubMed  CAS  Google Scholar 

  59. Shirley MA, Guan X, Kaiser DG, et al. Taurine conjugation of ibuprofen in humans and in rat liver in vitro. Relationship to metabolic chiral inversion. J Pharmacol Exp Ther 1994; 269: 1166–75

    PubMed  CAS  Google Scholar 

  60. Tanaka Y, Shimomura Y, Hirota T, et al. Formation of glycine conjugate and (−)-(R)-enantiomer from(+)-(S)-2-phenyl-propionic acid suggesting the formation of the CoA thioester intermediate of (+)-(S)-enantiomer in dogs. Chirality 1992; 4: 342–8

    Article  PubMed  CAS  Google Scholar 

  61. Upton RA, Buskin JN, Williams RL, et al. Negligible excretion of unchanged ketoprofen, naproxen and probenecid in urine. J Pharm Sci 1980; 69: 1254–7

    Article  PubMed  CAS  Google Scholar 

  62. Mroszczak E, Lee FW, Combs D, et al. Ketorolac tromethamine absorption, distribution, metabolism, excretion, and pharmacokinetics in animals and humans. Drug Metab Dispos 1987; 15: 618–26

    PubMed  CAS  Google Scholar 

  63. Mayo BC, Chasseaud LF, Hawkins DR, et al. The metabolic fate of 14C-ximoprofen in rats, baboons and humans. Xenobiotica 1990; 20: 233–46

    Article  PubMed  CAS  Google Scholar 

  64. Spahn-Langguth H, Benet LZ. Acyl glucuronides revisited: is the glucuronidation process a toxification as well as a detoxification mechanism? Drug Metab Rev 1992; 24: 5–48

    Article  PubMed  CAS  Google Scholar 

  65. Advenier C, Roux A, Gobert C, et al. Pharmacokinetics of ketoprofen in the elderly. Br J Clin Pharmacol 1983; 16: 65–70

    Article  PubMed  CAS  Google Scholar 

  66. Anttila M, Haataja M, Kasanan A. Pharmacokinetics of naproxen in subjects with normal and impaired renal function. Eur J Clin Pharmacol 1980; 18: 263–8

    Article  PubMed  CAS  Google Scholar 

  67. Foster RT, Jamali F, Russell AS. Pharmacokinetics of ketoprofen enantiomers in cholecystectomy patients: influence of probenecid. Eur J Clin Pharmacol 1989; 37: 589–94

    PubMed  CAS  Google Scholar 

  68. Meffin PJ, Sallustio BC, Purdie YJ, et al. Enantioselective disposition of 2-arylpropionic acid nonsteroidal anti-inflammatory drugs. I. 2-Phenylpropionic acid disposition. J Pharmacol Exp Ther 1986; 238: 280–7

    PubMed  CAS  Google Scholar 

  69. Hayball PJ. Formation and reactivity of acyl glucuronides: the influence of chirality. Chirality 1995; 7: 1–9

    Article  PubMed  CAS  Google Scholar 

  70. Peskar BM, Kluge S, Peskar BA, et al. Effects of pure enantiomers of flurbiprofen in comparison to racemic flurbiprofen on eicosanoid release from various rat organs ex vivo. Prostaglandins 1991; 42: 515–31

    Article  PubMed  CAS  Google Scholar 

  71. Wechter WJ, Bigornia AE, Murray ED, et al. Rac-flurbiprofen is more ulcerogenic than its (S)-enantiomer. Chirality 1993; 5: 492–4

    Article  PubMed  CAS  Google Scholar 

  72. Wallace JL, Granger DN. Pathogenesis of NSAID gastropathy: are neutrophils the culprits? Trends Pharm Sci 1992; 13: 129–31

    Article  PubMed  CAS  Google Scholar 

  73. Carson JL, Willett LR. Toxicity of nonsteroidal anti-inflammatory drugs. An overview of epidemiological evidence. Drugs 1993; 46 Suppl. 1: 243–8

    Article  PubMed  Google Scholar 

  74. Willett LR, Carson JL, Strom BL. Epidemiology of gastrointestinal damage associated with nonsteroidal anti-inflammatory drugs. Drug Saf 1994; 10: 170–81

    Article  PubMed  CAS  Google Scholar 

  75. Rainsford KD. Inhibitors of eicosanoid metabolism. In: Curtis-Prior PB, editor. Prostaglandins — biology and chemistry of prostaglandins and related eicosanoids. Edinburgh: Churchill Livingstone, 1988: 52–68

    Google Scholar 

  76. Kubota T, Komatsu H, Kawamoto H, et al. Studies on the effects of anti-inflammatory action of benzoyl-hydratropic acid (ketoprofen) and other drugs, with special reference to pros-taglandin synthesis. Arch Int Pharmacodyn Ther 1979; 237: 169–76

    PubMed  CAS  Google Scholar 

  77. Fears R, Richards DH. Association between lipid-lowering activity of aryl-substituted carboxylic acids and formation of substituted glycerolipids in rats. Biochem Soc Trans 1981; 9: 572–3

    CAS  Google Scholar 

  78. Caldwell J, Marsh MV. Interrelationship between xenobiotic metabolism and lipid biosynthesis. Biochem Pharmacol 1983; 32: 1667–72

    Article  PubMed  CAS  Google Scholar 

  79. Williams KM, Day RO. The contribution of enantiomers to variability in response to anti-inflammatory drugs. Agents Actions Suppl 1988; 24: 76–84

    PubMed  CAS  Google Scholar 

  80. Benet LZ, Spahn-Langguth H, Iwakawa S, et al. Predictability of the covalent binding of acidic drugs in man. Life Sci 1993; 53: PL141–6

    Article  PubMed  CAS  Google Scholar 

  81. Ding A, Ojingwa JC, McDonagh AF, et al. Evidence for covalent binding of acyl glucuronides to serum albumin via an imine mechanism as revealed by tandem mass spectrometry. Proc Natl Acad Sci USA 1993; 90: 3797–801

    Article  PubMed  CAS  Google Scholar 

  82. Yvon M, Wal J-M. Identification of lysine residue 199 of human serum albumin as a binding site for benzylpenicilloyl groups. FEBS Lett 1988; 239: 237–40

    Article  PubMed  CAS  Google Scholar 

  83. Smith PC, McDonagh AF, Benet LZ. Irreversible binding of zomepirac to plasma protein in vitro and in vivo. J Clin Invest 1986; 77: 934–9

    Article  PubMed  CAS  Google Scholar 

  84. Simkin PA. Concentration-effect relationships of NSAID. J Rheumatol 1988; 15 Suppl. 17: 40–3

    Google Scholar 

  85. Geisslinger G, Stock KP, Loew D, et al. Variability in the stereoselective disposition of ibuprofen in patients with rheumatoid arthritis. Br J Clin Pharmacol 1993; 35: 603–7

    Article  PubMed  CAS  Google Scholar 

  86. Birkett DJ. Racemates of enantiomers: regulatory approaches. Clin Exp Pharmacol Physiol 1989; 16: 479–83

    Article  PubMed  CAS  Google Scholar 

  87. Lennard MS. Clinical pharmacology through the looking glass: reflections on the racemate vs enantiomer debate. Br J Clin Pharmacol 1991; 31: 623–5

    Article  PubMed  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Pharmacy Department, Repatriation General Hospital, Daw Park, South Australia, Australia

    Peter Hayball

Authors
  1. Peter Hayball
    View author publications

    You can also search for this author in PubMed Google Scholar

Rights and permissions

Reprints and permissions

About this article

Cite this article

Hayball, P. Chirality and Nonsteroidal Anti-Inflammatory Drugs. Drugs 52 (Suppl 5), 47–58 (1996). https://doi.org/10.2165/00003495-199600525-00006

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.2165/00003495-199600525-00006

Keywords

Search

Navigation