Pharmacokinetics of ezlopitant, a novel non-peptidic neurokinin-1 receptor antagonist in preclinical species and metabolite kinetics of the pharmacologically active metabolites.

The pharmacokinetics of ezlopitant were determined in the rat, gerbil, guinea pig, ferret, dog and monkey after intravenous and oral administration. In general, ezlopitant is marked by high clearance values that approach or exceed hepatic blood flow values, moderate to high values for steady-state volume of distribution (3. 9-28 L/kg), and terminal phase half-life values ranging from 0.6 h in the guinea pig to 7.7 h in the rat. Oral bioavailability ranged from <0.2% (guinea pig) to 28% (dog). Data from portal vein cannulated dogs suggested that 37% of an oral dose of ezlopitant enters the portal vein as an unchanged drug in this species. Ezlopitant is metabolized to two pharmacologically active metabolites, an alkene (CJ-12 458) and a benzyl alcohol (CJ-12 764). After administration of the parent compound, CJ-12 764 was found in greater abundance than CJ-12 458 in all species examined. Ezlopitant and CJ-12 458 were highly protein bound in plasma (or serum), whereas the protein binding of CJ-12 764 was somewhat lower. Measurement of the kinetics of ezlopitant, CJ-12 458 and CJ-12 764 in the cerebrospinal fluid (CSF) of dogs demonstrated that all three compounds can partition into the CSF, and thereby, be capable of contributing to centrally mediated pharmacological effects. Thus, these data suggest that the pharmacological activity exhibited by ezlopitant in preclinical species in vivo is likely a result of the parent compound plus the active metabolites. Furthermore, the contributions of ezlopitant and the active metabolites to pharmacological activity probably varies with the identity of the model species, as well as the dose and route of ezlopitant administration. Copyright 1999 John Wiley & Sons, Ltd.