Disposition of the opioid antagonist, nalmefene, in rat and dog.

1. The disposition of nalmefene in rat and dog was studied using in vitro and in vivo methodology. In vitro metabolite profiles were obtained following incubation of nalmefene with liver microsomes and biological fluids were assayed to profile in vivo metabolites. Characterization of metabolites was accomplished using hplc, co-chromatography with synthetic standards, or LC/MS. 2. In rat, tissue distribution and metabolite plasma concentration-time data were obtained following intravenous 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 production was rat >> dog. In vivo, nornalmefene glucuronide was the major metabolite in rat urine, whereas nalmefene glucuronide(s) were predominant in dog urine. 4. More than 90% of the radioactive dose was recovered in the rat excreta and tissues 24 h after an intravenous bolus dose of 14C-nalmefene, with no apparent organ-specific retention of radioactivity. 5. Pharmacokinetic analysis of the rat plasma metabolite data indicated that terminal half-lives for nalmefene and nornalmefene were comparable (approximately 1 h). However, Cmax and AUC of nornalmefene were < or = 7% that of corresponding nalmefene values.

Determination of mirfentanil hydrochloride (A-3508.HCl) in human plasma by liquid chromatography-mass spectrometry.

A method for the quantitation of mirfentanil hydrochloride (A-3508.HCl) in human plasma is presented for the first time, using LC-MS with single ion monitoring. The drug is extracted with a C-18 solid-phase cartridge and the extract is analysed using a 3 cm C-18 column connected to the ion source of a mass spectrometer via a thermospray interface. The intense ion produced by the protonated molecular ion at m/z 377 is detected by the mass spectrometer in positive-ion mode. The range of quantitation is 0.4-100 ng ml-1 from a 0.5 ml plasma sample. Results of assay validation are given. The method was used to analyse samples from a human pharmacokinetic study following intravenous administration of mirfentanil hydrochloride.

Determination of [3H]brifentanil, a potent narcotic analgesic, from rat serum by high-performance liquid chromatography with on-line radioactive detection.

A method for rapid analysis of [3H]brifentanil extracted from rat serum is described that has the advantages of sensitivity, speed and specificity. The method is based on extraction from serum via solid-phase extraction followed by chromatographic separation on a reversed-phase high-performance liquid chromatographic column. Detection of [3H]brifentanil is accomplished with an on-line radioactive detector, thus the laborious step of peak collection and subsequent liquid scintillation counting is eliminated. The developed method is sensitive to 0.1 ng/ml and has been successfully applied to pharmacokinetic studies in rats. In vivo metabolites retaining the radiolabel have been detected with the method and were more polar than the parent compound as based upon the elution order on the reversed-phase system.