Pharmacokinetics and biologic activity of the novel mast cell inhibitor, 4-(3 '-hydroxyphenyl)amino-6,7-dimethoxyquinazoline in mice

Purpose, The purpose of the present study was to examine the pharmacodynami c and pharmacokinetic features of the novel mast cell inhibitor 4-(3'-Hydro xyphenyl)-amino-6,7-dimethoxyquinazoline (WHI-P180) in mice. Methods. A high performance liquid chromatography (HPLC)-based quantitative detection method was used to measure plasma WHI-P180 levels in mice. The p lasma concentration-time data was fit to a single compartment pharmacokinet ic model by using the WinNonlin program to calculate the pharmacokinetic pa rameters. A cutaneous anaphylaxis model was used to examine the pharmacodyn amic effects of WHI-P180 on anaphylaxis-associated vascular hyperpermeabili ty. Results. The elimination half-life of WHI-P180 in CD-1 mice (BALB/c mice) f ollowing i.v., i.p., or p.o. administration was less than 10 min. Systemic clearance of WHI-P180 was 6742 mL/h/kg in CD-1 mice and 8188 mL/h/kg in BAL B/c mice. Notably, WHI-P180, when administered in two consecutive nontoxic i.p. bolus doses of 25 mg/kg, inhibited IgE/antigen-induced vascular hyperp ermeability in a well-characterized murine model of passive cutaneous anaph ylaxis. Conclusions. WHI-P180 is an active inhibitor of IgE-mediated mast cell resp onses in vitro and in vivo. Further preclinical characterization of WHI-P18 0 may improve the efficacy of WHI-P180 in vivo and provide the basis for de sign of effective treatment and prevention programs for mast cell mediated allergic reactions.