C L Chen, R Malaviya, C Navara, H Chen, B Bechard, G Mitcheltree, X P Liu, F M Uckun
Department of Pharmaceutical Sciences, Hughes Institute, St. Paul, Minnesota 55113, USA.
Pharmaceutical research 1999 JanThe purpose of the present study was to examine the pharmacodynamic and pharmacokinetic features of the novel mast cell inhibitor 4-(3'-Hydroxyphenyl)-amino-6,7-dimethoxyquinazoline (WHI-P180) in mice. A high performance liquid chromatography (HPLC)-based quantitative detection method was used to measure plasma WHI-P180 levels in mice. The plasma concentration-time data was fit to a single compartment pharmacokinetic model by using the WinNonlin program to calculate the pharmacokinetic parameters. A cutaneous anaphylaxis model was used to examine the pharmacodynamic effects of WHI-P180 on anaphylaxis-associated vascular hyperpermeability. The elimination half-life of WHI-P180 in CD-1 mice (BALB/ c mice) following 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-I mice and 8188 mL/h/kg in BALB/c mice. Notably, WHI-P180, when administered in two consecutive nontoxic i.p. bolus doses of 25 mg/kg, inhibited IgE/antigen-induced vascular hyperpermeability in a well-characterized murine model of passive cutaneous anaphylaxis. WHI-P180 is an active inhibitor of IgE-mediated mast cell responses in vitro and in vivo. Further preclinical characterization of WHI-P180 may improve the efficacy of WHI-P180 in vivo and provide the basis for design of effective treatment and prevention programs for mast cell mediated allergic reactions.
C L Chen, R Malaviya, C Navara, H Chen, B Bechard, G Mitcheltree, X P Liu, F M Uckun. Pharmacokinetics and biologic activity of the novel mast cell inhibitor, 4-(3-hydroxyphenyl)-amino-6,7-dimethoxyquinazoline in mice. Pharmaceutical research. 1999 Jan;16(1):117-22
PMID: 9950289
View Full Text