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European Journal of Clinical Pharmacology

, Volume 43, Issue 4, pp 431–433 | Cite as

Dose-dependent kinetics of the enantiomers of MK-571, an LTD4-receptor antagonist

  • M. Depré
  • D. J. Margolskee
  • A. Van Hecken
  • J. S. Y. Hsieh
  • A. Buntinx
  • P. J. De Schepper
  • J. D. Rogers
Short Communications

Summary

The disposition of the enantiomers of MK-571 (MK-0679 and L-668,018) following single i. v. doses of MK-571 (L-660,711) was studied in a three way cross-over study in 12 healthy male volunteers. Each volunteer received 75 mg, 300 mg and 600 mg i. v. doses of MK-571 at weekly intervals.

The disposition of both enantiomers appeared dose-dependent, since the AUC increased disproportionately faster than the dose. The dose dependency was much more pronounced for L-668,018: its AUC increased 6-fold from the 75 to the 300 mg dose, 16-fold from 75 to 600 mg and 2.7 fold from 300 to 600 mg. For MK-0679, the corresponding increases in AUC were 4.8-, ll-, and 2.3 fold. Regardless of dose, the elimination of L-668,018 was more rapid than that of MK-0679.

The disposition of MK-0679 needs to be investigated independently to detect any potential influence of L-668,018 on its disposition.

Key words

MK-571, LTD4-receptor antagonist MK-0679, L-668,018, pharmacokinetics, enantiomers, healthy volunteers, pharmacokinetics 

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References

  1. Depré M, Margolskee DJ, Hsieh JYK, Van Hecken A, Buntinx A, De Lepeleire I, Rogers JD, De Schepper PJ (1992) Plasma drug profiles and tolerability of MK-571 (L-660,711), a leukotriene D4 receptor antagonist in man. Eur J Clin Pharmacol 43: 427–430PubMedGoogle Scholar
  2. Hendeles L, Davison D, Blake K, Harman E, Cooper R, Margolskee D (1990) Leukotriene D4 is an important mediator of antigen induced bronchoconstriction: attenuation of dual response with MK-571, a specific LTD4 receptor antagonist. J Allergy Clin Immunol 85: 197Google Scholar
  3. Kips JC, Joos GE, Lepeleire I De, Margolskee DJ, Buntinx A, Pauwels R, Straeten M Van Der (1990) MK-571: a potent antagonist of LTD4-induced bronchoconstriction in man. Am Rev Respir Dis 144: 617–621Google Scholar
  4. Manning PJ, Watson RM, Margolskee DJ, Williams VC, Schwartz JI (1990) Inhibition of exercise-induced bronchoconstriction by MK-571, a potent leukotriene D4-receptor antagonist. N Engl J Med 323: 1736–1739PubMedGoogle Scholar
  5. Margolskee DJ (1991) Clinical experience with MK-571: a potent and specific LTD4-receptor antagonist. Ann NY Acad Sci 629: 148–156PubMedGoogle Scholar
  6. Robinett R, Hsieh JYK (1991) Stereoselective determination of R(−) and S(+) MK-571 in human plasma by chiral high performance liquid chromatography. J Chromatogr Biomed Applic 570: 157–165Google Scholar

Copyright information

© Springer-Verlag 1992

Authors and Affiliations

  • M. Depré
    • 1
  • D. J. Margolskee
    • 2
    • 3
    • 4
  • A. Van Hecken
    • 1
  • J. S. Y. Hsieh
    • 2
    • 3
    • 4
  • A. Buntinx
    • 2
    • 3
    • 4
  • P. J. De Schepper
    • 1
  • J. D. Rogers
    • 2
    • 3
    • 4
  1. 1.Department of Pharmacology, School of Medicine and School of PharmacyUniversity of LeuvenLeuvenBelgium
  2. 2.Merck Sharp & Dohme Research LaboratoriesBrusselsBelgium
  3. 3.West Point
  4. 4.RahwayUSA

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