RT Journal Article
SR Electronic
T1 Substance P Receptor Antagonist I: Conversion of Phosphoramidate Prodrug after i.v. Administration to Rats and Dogs
JF Drug Metabolism and Disposition
JO Drug Metab Dispos
FD American Society for Pharmacology and Experimental Therapeutics
SP 1367
OP 1373
VO 27
IS 11
A1 Huskey, Su-Er W.
A1 Luffer-Atlas, Debra
A1 Dean, Brian J.
A1 McGowan, Erin M.
A1 Feeney, William P.
A1 Chiu, Shuet-Hing Lee
YR 1999
UL http://dmd.aspetjournals.org/content/27/11/1367.abstract
AB A water-soluble phosphoramidate prodrug (L-758,298, compound I) of the potent 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 acidic conditions. In the studies reported herein, we investigated the stability of I in blood and hepatic subcellular fractions from rats, dogs, and humans 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 prepared 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 rats and dogs. The relative extent of exposure of II after i.v. dosing of I was estimated by comparing the dose-adjusted area under the plasma concentration 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 ∼90 and ∼100% at 1 and 8 mg/kg, respectively; in dogs, that was ∼59% at 0.5 mg/kg. A nonproportional increase in the area under 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 that the elimination of II might have been saturated at higher doses. The American Society for Pharmacology and Experimental Therapeutics