Abstract

The in vivo pharmacology of ICI 198,615, a highly potent and selective peptide leukotriene (LT) receptor antagonist, is described. In a conscious guinea pig model, ICI 198,615 provided dose-related antagonism of aerosol LTD4-induced dyspnea when administered p.o., i.v. or by aerosol. The pharmacologic half-lives of ICI 198,615 by these routes of administration were greater than 16 hr, 68 min and 34 min, respectively. In pulmonary mechanics studies in which the effects of i.v. or aerosol administration of LTC4 and LTD4 on pulmonary resistance (Rp) or dynamic lung compliance (Cdyn) could be quantitated, ICI 198,615 provided dose-related antagonism when administered p.o., i.d, i.v. or by aerosol. The compound also antagonized LTE4-induced changes in Rp and Cdyn when administered i.v. ICI 198,615 reversed the effect of LTC4, LTD4 and LTE4 on Rp, as well as the effect of LTC4 and LTE4 on Cdyn. The compound was less able to reverse the effect of LTD4 on Cdyn. These results indicate that ICI 198,615 possesses an in vivo profile which is consonant with utility in the treatment of allergic diseases.