Substance P receptor antagonist I: Conversion of phosphoramidate prodrug after i.v. administration to rats and dogs

A water-soluble phosphoramidate prodrug (L-758,298, compound I) of the pote nt and selective human Substance P receptor antagonist L-754,030 (compound II) is under development as an i.v. drug for treatment of emesis, migraine, and chronic pain. Compound I undergoes hydrolysis readily to II under acid ic conditions. In the studies reported herein, we investigated the stabilit y of I in blood and hepatic subcellular fractions from rats, dogs, and huma ns as well as the conversion of I to II in rats and dogs after i.v. dosing. Compound I was converted to II rapidly in rat blood but was stable in dog and human blood. However, the conversion was rapid in liver microsomes prep ared from dogs and humans. As expected from the results of in vitro studies , the in vivo conversion of I to II was rapid after i.v. dosing of I to rat s and dogs. The relative extent of exposure of II after i.v. dosing of I wa s estimated by comparing the dose-adjusted area under the plasma concentrat ion versus time curve values of II after i.v. dosing of I with those after i.v. dosing of II. In rats, the extent of exposure was estimated to be simi lar to 90 and similar to 100% at 1 and 8 mg/kg, respectively; in dogs, that was similar to 59% at 0.5 mg/kg. A nonproportional increase in the area un der the concentration versus time curve value of II with dose was observed after i.v. administration of I in dogs from 0.5 to 32 mg/kg, suggesting tha t the elimination of II might have been saturated at higher doses.