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Lack of Pharmacokinetic Interaction between Zileuton and Phenytoin in Humans

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Summary

A randomised double-blind crossover study was undertaken in 20 healthy adult male volunteers to assess the effects of multiple oral dose administration of zileuton (600mg every 6 hours for 8 days) on the single dose pharmacokinetics of phenytoin 300mg. Serial blood samples were collected up to 72 hours after phenytoin administration and plasma concentrations were determined by high performance liquid chromatography. Pharmacokinetic data were analysed utilising noncompartmental and Michaelis-Menten-based population pharmacokinetic analysis.

Zileuton did not significantly alter the peak plasma concentration, time to peak plasma concentration, and area under the plasma concentration-time curve of phenytoin. Moreover, population analysis revealed no significant effect of zileuton on the Michaelis-Menten parameters of phenytoin. Thus, coadministration of multiple doses of zileuton (2.4 g/day) did not significantly affect the single dose pharmacokinetics of phenytoin.

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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 1911; 256: 929–37

    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 Pharmacol 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. Euro J Pharmacol 1991; 205: 259–66

    Article  CAS  Google Scholar 

  10. 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 

  11. 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 

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

    Article  PubMed  CAS  Google Scholar 

  13. 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 

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

    Article  PubMed  CAS  Google Scholar 

  15. 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 

  16. 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 

  17. Tozer TN, Winter ME. Phenytoin. In: Evans et al., editors. Applied pharmacokinetics. Principles of therapeutic drug monitoring. 3rd ed. Vancouver: Applied Therapeutics Inc., 1992: 25–1–25–44

    Google Scholar 

  18. Nation RL, Evans AM, Milne RW. Pharmacokinetic drug interactions with phenytoin. Clin Pharmacokinet 1990; 18: 37–60, 131–50

    Article  PubMed  CAS  Google Scholar 

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

    Article  PubMed  CAS  Google Scholar 

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

    Google Scholar 

  21. Beal S, Sheiner L. NONMEM Users Guide, NONMEM version IV. Project Group, University of California, San Francisco, 1989

  22. Awni WM, Braeckman RA, Cavanaugh JH, et al. The pharmacokinetic and pharmacodynamic interactions between the 5-lipoxygenase inhibitor zileuton and and the cyclo-oxygenase inhibitor naproxen in human volunteers. Clin Pharmacokinet 1995; 29 Suppl. 2: 112–24

    Article  PubMed  CAS  Google Scholar 

  23. Awni WM, Hussein Z, Granneman GR, et al. Pharmacodynamic and sterioselective pharmacokinetic interactions between zileuton and warfarin in humans. Clin Pharmacokinet 1995; 29 Suppl. 2: 67–76

    Article  PubMed  CAS  Google Scholar 

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Authors and Affiliations

  1. Pharmacokinetics and Biopharmaceutics Department, Abbott Laboratories 4PK, AP13A, 100 Abbott Park Road, Abbott Park, Illinois, 60064-3500, USA

    Emil Samara & G. Richard Granneman

  2. Clinical Pharmacology Department, Abbott Laboratories, Abbott Park, Illinois, USA

    John H. Cavanaugh

  3. Clinical Statistics Department, Abbott Laboratories, Abbott Park, Illinois, USA

    Debabrata Mukherjee

Authors
  1. Emil Samara
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  2. John H. Cavanaugh
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  3. Debabrata Mukherjee
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  4. G. Richard Granneman
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Samara, E., Cavanaugh, J.H., Mukherjee, D. et al. Lack of Pharmacokinetic Interaction between Zileuton and Phenytoin in Humans. Clin-Pharmacokinet 29 (Suppl 2), 84–91 (1995). https://doi.org/10.2165/00003088-199500292-00012

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