LTB4-INDUCED TRANSIENT NEUTROPENIA IN THE RAT - A MODEL FOR EVALUATING EFFICACY AND BIOAVAILABILITY OF LTB4 RECEPTOR ANTAGONISTS

An animal model of leukotriene B4- (LTB4) induced neutropenia has been developed to evaluate LTB4 receptor antagonists in vivo. LTB4, a pote nt chemotactic inflammatory mediator, when administered intravenously, induces a profound, rapid, and transient redistribution of blood neut rophils from the circulating pool to the marginated pool. This phenome non is applied in the neutropenia model whereby circulating blood neut rophil counts prior to and after intravenous infusion of LTB4 are comp ared. Kinetics of LTB4-induced neutrophil responses are determined thr ough the use of a Technicon H1 automated blood cell analyzer. LTB4 re ceptor antagonists are identified by inhibition of LTB4-induced neutro penia. Standard antiinflammatory compounds including BW-755C, Abbott A -64077 (zileuton), dexamethasone-21-acetate, indomethacin, and naproxe n did not affect LTB4-induced neutropenia. A potent LTB4 receptor anta gonist, designated ''RPR,'' inhibited LTB4-induced neutropenia followi ng oral administration in a dose-dependent fashion.