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Pharmacodynamic and Stereoselective Pharmacokinetic Interactions between Zileuton and Warfarin in Humans

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Summary

A double-blind parallel randomised study was conducted to assess the effects of multiple oral doses of zileuton (600mg every 6 hours) or matching placebo on the steady-state pharmacokinetics and pharmacodynamics of warfarin titrated to a prothrombin time of 14 to 18 seconds in 24 healthy adult male volunteers.

Serial blood samples were collected for assessment of prothrombin times and R- and S- warfarin plasma concentrations.

Coadministration of zileuton and warfarin had no effect on S-warfarin pharmacokinetics but statistically significantly increased mean R-warfarin plasma concentrations and decreased mean R-warfarin total oral plasma clearance compared with warfarin alone (by 15%). This stereoselective interaction was accompanied by an increase in mean morning (predose) and evening (12-hour postdose) prothrombin times from 17.5 to 19.8 seconds and 17.1 to 19.1 seconds, respectively; the corresponding changes in the placebo group were from 18.1 to 18.8 seconds and 17.3 to 17.5 seconds.

Thus, multiple dose administration of zileuton appears to significantly alter steady-state R-warfarin pharmacokinetics and pharmacodynamics. Careful monitoring of prothrombin times with appropriate dose titration of warfarin is recommended with concurrent therapy of zileuton and warfarin.

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References

  1. Bell RL, Young PR, Albert D, et al. The discovery and development of zileuton: an orally active 5-lipoxygenase inhibitor. Int J Immunopharmacol 1992; 14: 505–10

    Article  PubMed  CAS  Google Scholar 

  2. Batt DG. 5-Lipoxygenase inhibitors and their anti-inflammatory activities. Prog Med Chem 1992; 29: 1–63

    Article  PubMed  CAS  Google Scholar 

  3. Carter GW, Young PR, Albert DH, et al. 5-Lipoxygenase inhibitory activity of zileuton. J Pharmacol Exp Ther 1991; 256: 929–37

    PubMed  CAS  Google Scholar 

  4. Noonan TC, Jamieson-Leclercq T, Desai SV. Effect of BI-L-239, A-64077 and MK-886 on leukotriene B4 synthesis by chopped guinea pig lung and on antigen-induced tracheal contraction in vitro. Prostaglandins 1992; 44: 543–54

    PubMed  CAS  Google Scholar 

  5. Riendeau D, Guay J, Foster A, et al. Inhibition of leukotriene B4 biosynthesis by disulfiram and A-64077 during carrageenan-induced pleurisy in the rat. Gen Pharmacol 1991; 22: 371–4

    Article  PubMed  CAS  Google Scholar 

  6. Rubin P, Kesterson J, Swanson L, et al. Safety, pharmacokinetics and leukotriene B4 (LTB4) inhibition of single doses of A-64077 in normal male volunteers [abstract IVC-1]. Clin Pharm Ther 1989; 45: 187

    Google Scholar 

  7. Rubin P, Dubé L, Braeckman R, et al. Pharmacokinetics, safety, and ability to diminish leukotriene synthesis by zileuton, an inhibitor of 5-lipoxygenase. Agents Actions 1991; 35:103–16

    CAS  Google Scholar 

  8. Sirois P, Borgeat P, Lauziere M, et al. Effect of zileuton (A-64077) on the 5-lipoxygenase activity of human whole blood ex vivo. Agents Actions 1991; 34: 117–20

    Article  PubMed  CAS  Google Scholar 

  9. Young PR, Bell RL, Lanni C, et al. Inhibition of leukotriene biosynthesis in the rat peritoneal cavity. Eur J Pharmacol 1991; 205: 259–66

    Article  PubMed  CAS  Google Scholar 

  10. Bukhave K, Laursen LS, Lauritsen K, et al. 5-Lipoxygenase inhibition in double-blind trial with zileuton: how much is sufficient in active ulcerative colitis? [abstract]. Gastroenterology 1991; 100: A200

    Google Scholar 

  11. Collawn C, Rubin P, Perez N, et al. Phase II study of the safety and efficacy of a 5-lipoxygenase inhibitor in patients with ulcerative colitis. Am J Gastroenterol 1992; 87: 342–6

    PubMed  CAS  Google Scholar 

  12. Frossard N, LeGall G, Cohn J. Effect of a 5-lipoxygenase inhibitor, zileuton, on the immunologically-induced contraction of human bronchi [abstract]. Am Rev Respir Dis 1992; 145:A289

    Google Scholar 

  13. Hui KP, Taylor IK, Taylor GW, et al. Effect of a 5-lipoxygenase inhibitor on leukotriene generation and airway responses after allergen challenge in asthmatic patients. Thorax 1991; 46: 184–9

    Article  PubMed  CAS  Google Scholar 

  14. Israel E, Dermarkarian R, Rosenberg M, et al. The effects of a 5-lipoxygenase inhibitor on asthma induced by cold, dry air. N Engl J Med 1990; 323: 1740–4

    Article  PubMed  CAS  Google Scholar 

  15. Israel E, Rubin P, Pearlman H, et al. 5-Lipoxygenase inhibition by zileuton causes acute bronchodilation in asthma [abstract]. Am Rev Respir Dis 1992; 145: A16

    Google Scholar 

  16. Israel E, Rubin P, Kemp JP, et al. The effect of inhibition of 5-lipoxygenase by zileuton in mild-to-moderate asthma. Ann Intern Med 1993; 119: 1059–66

    PubMed  CAS  Google Scholar 

  17. Knapp HR. Reduced allergen-induced nasal congestion and leukotriene synthesis with an orally active 5-lipoxygenase inhibitor. N Engl J Med 1990; 323: 1745–8

    Article  PubMed  CAS  Google Scholar 

  18. Laursen LS, Naesdal J, Bukhave K, et al. Selective 5-lipoxygenase inhibition in ulcerative colitis. Lancet 1990; 335: 683–5

    Article  PubMed  CAS  Google Scholar 

  19. Stenson WF, Lauritsen K, Laursen LS, et al. A clinical trial of zileuton, a specific inhibitor of 5-lipoxygenase, in ulcerative colitis [abstract]. Gastroenterology 1991; 100: A253

    Google Scholar 

  20. Weinblatt ME, Kremer JM, Coblyn JS, et al. Zileuton, a 5-lipoxygenase inhibitor in rheumatoid arthritis. J Rheumatol 1992; 19: 1537–41

    PubMed  CAS  Google Scholar 

  21. Breckenridge AM, Orme M, Wesseling H, et al. Pharmacokinetics and pharmacodynamics of the enantiomers of warfarin in man. Clin Pharmacol Ther 1974; 15: 424–30

    PubMed  CAS  Google Scholar 

  22. Hewick DS, McEwen J. Plasma half-lives, plasma metabolites and anticoagulant efficacies of the enantiomers of warfarin in man. J Pharm Pharmacol 1973; 25: 458–65

    Article  PubMed  CAS  Google Scholar 

  23. Holford NHG. Clinical pharmacokinetics and pharmacodynamics of warfarin. Understanding the dose-effect relationship. Clin Pharmacokinet 1986; 11: 483–504

    Article  PubMed  CAS  Google Scholar 

  24. Kelly JG, O’Malley K. Clinical pharmacokinetics of oral anticoagulants. Clin Pharmacokinet 1979; 4: 1–15

    Article  PubMed  CAS  Google Scholar 

  25. Granneman GR, Braeckman RA, Locke C, et al. Effect of zileuton on theophylline pharmacokinetics. Clin Pharmacokinet 1995; 29 Suppl. 2: 77–83

    Article  PubMed  CAS  Google Scholar 

  26. St Peter JV, Braeckman RA, Granneman GR, et al. The effect of zileuton on antipyrine and indocyanine green disposition. Clin Pharm Ther 1995; 57: 299–308

    Article  Google Scholar 

  27. Banfield C, Rowland M. Stereospecific fluorescence highperformance liquid Chromatographic analysis of warfarin and its metabolites in plasma and urine. J Pharm Sci 1984; 73: 1392–6

    Article  PubMed  CAS  Google Scholar 

  28. Sutfin T, Balmer K, Bostum H, et al. Stereoselective interaction of omeprazole with warfarin in healthy men. Ther Drug Monit 1989; 11: 176–84

    Article  PubMed  CAS  Google Scholar 

  29. Gibaldi M, Perrier D, editors. Pharmacokinetics. 2nd ed. New York: Marcel Dekker, 1982

    Google Scholar 

  30. Machinist JM, Kukulka MJ, Bopp BA. In vitro plasma protein binding of zileuton and its N-dehydroxylated metabolite. Clin Pharmacokinet 1995; 29 Suppl.2: 34–41

    Article  Google Scholar 

  31. Rettie AE, Korzekwa KR, Kunze KL, el al. Hydroxylation of warfarin by human cDNA expressed cytochrome P-450: a role for P-4502C9 in the etiology of (S)-warfarin drug interaction. Chem Res Toxicol 1992; 5: 54–9

    Article  PubMed  CAS  Google Scholar 

  32. Toon S, Low LK, Gibaldi M, et al. Warfarin-sulfinpyrazone interaction: stereochemical considerations. Clin Pharm Ther 1986; 39: 15–24

    Article  CAS  Google Scholar 

  33. Lewis RJ, Trager WF, Chan KK, et al. Warfarin: stereochemical aspects of its metabolism and the interaction with phenylbutazone. J Clin Invest 1974; 53: 1607–17

    Article  PubMed  CAS  Google Scholar 

  34. Toon S, Hopkins KJ, Garstang FM, et al. The warfarin cimetidine interaction: stereochemical considerations. Br J Clin Pharmacol 1986; 21: 245–56

    Article  PubMed  CAS  Google Scholar 

  35. Toon S, Hopkins KJ, Garstang FM, et al. Enoxacin-warfarin interaction: pharmacokinetic and stereochemical aspects. Clin Pharm Ther 1987; 42: 33–41

    Article  Google Scholar 

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Authors and Affiliations

  1. Department of Pharmacokinetics and Biopharmaceutics, Abbott Laboratories D4PK, AP13A, 100 Abbott Park Road, Abbott Park, Illinois, 60064-3500, USA

    Walid M. Awni, Ziad Hussein & G. Richard Granneman

  2. Department of Statistics, Abbott Laboratories, Abbott Park, Illinois, USA

    Karen J. Patterson

  3. The Immunoscience Venture, Abbott Laboratories, Abbott Park, Illinois, USA

    Louise M. Dubé

  4. Department of Clinical Pharmacology, Abbott Laboratories, Abbott Park, Illinois, USA

    John H. Cavanaugh

Authors
  1. Walid M. Awni
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  2. Ziad Hussein
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  3. G. Richard Granneman
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  4. Karen J. Patterson
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  5. Louise M. Dubé
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  6. John H. Cavanaugh
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Awni, W.M., Hussein, Z., Granneman, G.R. et al. Pharmacodynamic and Stereoselective Pharmacokinetic Interactions between Zileuton and Warfarin in Humans. Clin-Pharmacokinet 29 (Suppl 2), 67–76 (1995). https://doi.org/10.2165/00003088-199500292-00010

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  • DOI: https://doi.org/10.2165/00003088-199500292-00010

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