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Biochemical activity, pharmacokinetics, and tolerability of MK‐886, a leukotriene biosynthesis inhibitor, in humans
Author(s) -
Depre Marleen,
Friedman Beth,
Tanaka Wesley,
Hecken Anne Van,
Buntinx Agnes,
DeSchepper Paul J
Publication year - 1993
Publication title -
clinical pharmacology and therapeutics
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.941
H-Index - 188
eISSN - 1532-6535
pISSN - 0009-9236
DOI - 10.1038/clpt.1993.76
Subject(s) - ex vivo , leukotriene b4 , in vivo , pharmacology , leukotriene , whole blood , pharmacokinetics , chemistry , biosynthesis , placebo , tolerability , medicine , in vitro , biochemistry , biology , adverse effect , enzyme , inflammation , microbiology and biotechnology , alternative medicine , pathology , asthma
MK‐886, a leukotriene biosynthesis inhibitor, was evaluated in double‐blind, placebo‐controlled, randomized single‐ and multiple‐dose studies in 12 and 24 healthy male subjects, respectively. The effects of a single dose (250, 500, and 750 mg) and multiple doses (100 mg and 250 mg every 8 hours) of MK‐886 on calcium ionophore stimulated leukotriene B 4 synthesis ex vivo in whole blood were evaluated. Inhibition of leukotriene B 4 biosynthesis ex vivo occurred in a dose‐related manner up to a 500 mg single dose, and 250 mg every 8 hours. A single dose of 500 mg MK‐886 significantly inhibited leukotriene B 4 biosynthesis by a maximum of 60% at 2 hours after the dose (p < 0.05). Multiple doses of 250 mg significantly inhibited leukotriene B 4 biosynthesis by a maximum of 52% at 2 hours after the dose (p < 0.05). The degree of leukotriene B 4 inhibition ex vivo in whole blood significantly correlated with plasma MK‐886 concentrations (r = 0.78). In conclusion, the single and multiple doses of MK‐886 evaluated in this study were well tolerated overall and partially inhibited leukotriene B 4 biosynthesis ex vivo in whole blood. Clinical Pharmacology and Therapeutics (1993) 53, 602–607; doi: 10.1038/clpt.1993.76