In vivo | WHI-P97 was very well tolerated in mice, with no signs of toxicity at dose levels ranging from 5 μg/kg to 50 mg/kg, and LD10was not reached at a 50 mg/kg dose level when administered as a single i.p. or i.v. bolus dose. Therapeutic WHI-P97 concentrations, which inhibit mast cell leukotriene synthesis in vitro, could easily be achieved in vivo after the i.v. or i.p. administration of a single nontoxic 40 mg/kg bolus dose of WHI-P97. WHI-P97 showed promising biological activity in a mouse model of allergic asthma at nontoxic dose levels. Treatment of ovalbumin-sensitized mice with WHI-P97 prevented the development of airway hyper-responsiveness to methacholine in a dose-dependent fashion. WHI-P97 inhibited the eosinophil recruitment to the airway lumen after the ovalbumin challenge in a dose-dependent fashion. WHI-P97 had an elimination half-life (t1/2) of 58.9 min and systemic clearance (CL) of 891 ml/h/kg in CD-1 mice and a t1/2 of 84.2 min and CL of 1513 ml/h/kg in BALB/c mice. The values for AUC and Cmaxwere 107.3 μM·h and 296.7 μM, respectively, in CD-1 mice, and 58.4 μM·h and 212.7 μM, respectively, in BALB/c mice. The large volume of distribution [322 ml/kg in CD-1 mice and 415 ml/kg in BALB/c mice; ∼6-fold greater than the plasma volume (50 ml/kg)] suggests that WHI-P97 may be extensively partitioned into extravascular compartments[1]. |
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