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Quantitative high-performance liquid chromatographic method for pharmacokinetic studies of the potent mast cell inhibitor 4-(4'-hydroxyphenyl)amino-6,7-dimethoxyquinazoline (WHI-P131). 1999

C L Chen, and R Malaviya, and H Chen, and X P Liu, and F M Uckun
Department of Pharmaceutical Sciences, Hughes Institute, St. Paul, MN 55113, USA.

The novel quinazoline derivative 4-(4'-hydroxyphenyl)amino-6,7-dimethoxyquinazoline (WHI-P131) has recently been identified as a potent mast cell inhibitor capable of preventing IgE/antigen induced cutaneous as well as systemic fatal anaphylaxis in mice. Here we describe a sensitive high-performance liquid chromatography (HPLC)-based quantitative detection method for measurement of WHI-P131 levels in plasma as well as in target mast cells. The average extraction recovery for WHI-P131 was 88.4% for plasma and 75.7% for RBL-2H3 mast cell lysates. Good linearity (r>0.999) was observed throughout the concentration range of 0.1-20 microM in plasma and 0.01-5 nmol in 5 x 10(6) cells (0.5-238 microM per cell) for WHI-P131. Intra- and inter-assay variabilities were <7% and the lowest detection limit of WHI-P131 was 0.05 microM in plasma and 0.005 nmol in 5 million cells, respectively, at a signal-to-noise ratio of approximately 2. The practical utility of this new HPLC method was confirmed in a pilot pharmacokinetic study in BALB/c mice as well as in a cellular drug uptake and disposition study in RBL-2H3 mast cells. After intraperitoneal administration of a non-toxic 40 mg/kg bolus dose of WHI-P131, the estimated maximum plasma concentration was 92.7 microM, which is approximately 1-log higher than the effective in vitro mast cell inhibitory concentrations of WHI-P131. The drug absorption was rapid with an absorption half-life of only 2.9 min and the estimated time to reach the maximum plasma concentration was 8.3 min. WHI-P131 was cleared with an apparent systemic clearance rate of 2586 ml/h/kg and an elimination half-life of 1.8 h. An intracellular exposure level (AUC) of 55 microM x h was obtained after in vitro treatment of RBL-2H3 mast cells with WHI-P131 at a 33.6 microM final concentration in culture medium. The availability of the described quantitative HPLC detection method for WHI-P131 provides the basis for further development of WHI-P131 as an anti-allergic drug through detailed pharmacodynamic studies in preclinical animal models.

UI MeSH Term Description Entries
D008407 Mast Cells Granulated cells that are found in almost all tissues, most abundantly in the skin and the gastrointestinal tract. Like the BASOPHILS, mast cells contain large amounts of HISTAMINE and HEPARIN. Unlike basophils, mast cells normally remain in the tissues and do not circulate in the blood. Mast cells, derived from the bone marrow stem cells, are regulated by the STEM CELL FACTOR. Basophils, Tissue,Basophil, Tissue,Cell, Mast,Cells, Mast,Mast Cell,Tissue Basophil,Tissue Basophils
D008807 Mice, Inbred BALB C An inbred strain of mouse that is widely used in IMMUNOLOGY studies and cancer research. BALB C Mice, Inbred,BALB C Mouse, Inbred,Inbred BALB C Mice,Inbred BALB C Mouse,Mice, BALB C,Mouse, BALB C,Mouse, Inbred BALB C,BALB C Mice,BALB C Mouse
D010865 Pilot Projects Small-scale tests of methods and procedures to be used on a larger scale if the pilot study demonstrates that these methods and procedures can work. Pilot Studies,Pilot Study,Pilot Project,Project, Pilot,Projects, Pilot,Studies, Pilot,Study, Pilot
D011799 Quinazolines A group of aromatic heterocyclic compounds that contain a bicyclic structure with two fused six-membered aromatic rings, a benzene ring and a pyrimidine ring. Quinazoline
D002460 Cell Line Established cell cultures that have the potential to propagate indefinitely. Cell Lines,Line, Cell,Lines, Cell
D002851 Chromatography, High Pressure Liquid Liquid chromatographic techniques which feature high inlet pressures, high sensitivity, and high speed. Chromatography, High Performance Liquid,Chromatography, High Speed Liquid,Chromatography, Liquid, High Pressure,HPLC,High Performance Liquid Chromatography,High-Performance Liquid Chromatography,UPLC,Ultra Performance Liquid Chromatography,Chromatography, High-Performance Liquid,High-Performance Liquid Chromatographies,Liquid Chromatography, High-Performance
D006207 Half-Life The time it takes for a substance (drug, radioactive nuclide, or other) to lose half of its pharmacologic, physiologic, or radiologic activity. Halflife,Half Life,Half-Lifes,Halflifes
D000818 Animals Unicellular or multicellular, heterotrophic organisms, that have sensation and the power of voluntary movement. Under the older five kingdom paradigm, Animalia was one of the kingdoms. Under the modern three domain model, Animalia represents one of the many groups in the domain EUKARYOTA. Animal,Metazoa,Animalia
D012680 Sensitivity and Specificity Binary classification measures to assess test results. Sensitivity or recall rate is the proportion of true positives. Specificity is the probability of correctly determining the absence of a condition. (From Last, Dictionary of Epidemiology, 2d ed) Specificity,Sensitivity,Specificity and Sensitivity
D015203 Reproducibility of Results The statistical reproducibility of measurements (often in a clinical context), including the testing of instrumentation or techniques to obtain reproducible results. The concept includes reproducibility of physiological measurements, which may be used to develop rules to assess probability or prognosis, or response to a stimulus; reproducibility of occurrence of a condition; and reproducibility of experimental results. Reliability and Validity,Reliability of Result,Reproducibility Of Result,Reproducibility of Finding,Validity of Result,Validity of Results,Face Validity,Reliability (Epidemiology),Reliability of Results,Reproducibility of Findings,Test-Retest Reliability,Validity (Epidemiology),Finding Reproducibilities,Finding Reproducibility,Of Result, Reproducibility,Of Results, Reproducibility,Reliabilities, Test-Retest,Reliability, Test-Retest,Result Reliabilities,Result Reliability,Result Validities,Result Validity,Result, Reproducibility Of,Results, Reproducibility Of,Test Retest Reliability,Validity and Reliability,Validity, Face

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