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Pharmacokinetics and Biologic Activity of the Novel Mast Cell Inhibitor, 4-(3-hydroxyphenyl)-amino-6,7-dimethoxyquinazoline in Mice

Pharmacokinetics and Biologic Activity of the Novel Mast Cell Inhibitor, 4-(3-hydroxyphenyl)-amino-6,7-dimethoxyquinazoline in Mice

C L Chen, R Malaviya, C Navara, H Chen, B Bechard, G Mitcheltree, X P Liu, F M Uckun

Pharm Res. 1999 Jan;16(1):117-22.

PMID: 9950289

Abstract:

Purpose:
The 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.
Methods:
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.
Results:
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.
Conclusions:
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.

Chemicals Related in the Paper:

Catalog Number	Product Name	Structure	CAS Number	Price
AP211555087	WHI-P180		211555-08-7	Price

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