DISPOSITION OF THE OPIOID ANTAGONIST, NALMEFENE, IN RAT AND DOG

1. The disposition of nalmefene in rat and dog was studied using in vi tro and in vivo methodology. In vitro metabolite profiles were obtaine d following incubation of nalmefene with liver microsomes and biologic al fluids were assayed to profile in vivo metabolites. Characterizatio n of metabolites was accomplished using hplc, co-chromatography with s ynthetic standards, or LC/MS. 2. In rat, tissue distribution and metab olite plasma concentration-time data were obtained following intraveno us bolus dosing of nalmefene. 3. The results indicate that the primary phase I metabolite of nalmefene from liver microsome incubations was the N-dealkylated metabolite, nornalmefene. Quantitative metabolite pr oduction was rat much greater than dog. In vivo, nornalmefene glucuron ide was the major metabolite in rat urine, whereas nalmefene glucuroni de(s) were predominant in dog urine. 4. More than 90 % of the radioact ive dose was recovered in the rat excreta and tissues 24 h after an in travenous bolus dose of C-14-nalmefene, with no apparent organ-specifi c retention of radioactivity. 5. Pharmacokinetic analysis of the rat p lasma metabolite data indicated that terminal half-lives for nalmefene and nornalmefene were comparable (similar to 1 h). However, C-max and AUC of nornalmefene were less than or equal to 7 % that of correspond ing nalmefene values.