In vivo pharmacokinetics and anti-anaphylactic activity of the novel mast cell inhibitor 4-(4'-hydroxylphenyl)-amino-6,7-dimethoxyquinazoline (WHI-P131).
WHI-P131 is a novel dimethoxyquinazoline compound that is a potent inhibitor of Janus kinase-3-(JAK3)-dependent mast cell responses. In the present study, the authors investigated the anti-anaphylactic activity and pharmacokinetics of WHI-P131 in mice. After intraperitoneal (i.p.) administration of two consecutive bolus doses of 25 mg/kg injected 30 min apart at dose level of 25 mg/kg, WHI-P131 was rapidly absorbed with an observed C(max) of 82.6 microM, which is higher than the target concentration of 30 microM, at which WHI-P131 abrogates mast cell responses in vitro and the time to reach the maximum plasma concentration (t(max)) was 10.0+/-2.9 min. At a nontoxic 50 mg/kg dose level, WHI-P131 prevented compound 48/80-induced mast cell histamine release and fatal anaphylaxis in mice. Further development of WHI-P131 may provide the basis for new and effective treatment as well as prevention programs for mast cell mediated allergic reactions in clinical settings.
Malavija
R
R
Department of Allergy, Parker Hughes Institute, St. Paul, MN, USA.
Chen
C L
CL
Liu
X P
XP
Uckun
F M
FM
D000707:Anaphylaxis / Q000188:drug therapy* / Q000276:immunology; D000818:Animals; D000970:Antineoplastic Agents / Q000276:immunology / Q000493:pharmacokinetics* / Q000494:pharmacology; D006632:Histamine / Q000032:analysis; D007263:Infusions, Parenteral; D008297:Male; D008407:Mast Cells / Q000187:drug effects; D051379:Mice; D008807:Mice, Inbred BALB C; D011799:Quinazolines / Q000276:immunology / Q000493:pharmacokinetics* / Q000494:pharmacology
D000970:Antineoplastic Agents; D011799:Quinazolines; C116180:WHI P131; D006632:Histamine