Novel carbamate metabolites of mofegiline, a primary amine monoamine oxidase B inhibitor, in dogs and humans
Dow, J; Piriou, F; Wolf, E; Dulery, BD; Haegele, KD
| HERO ID | 1943613 |
|---|---|
| In Press | No |
| Year | 1994 |
| Title | Novel carbamate metabolites of mofegiline, a primary amine monoamine oxidase B inhibitor, in dogs and humans |
| Authors | Dow, J; Piriou, F; Wolf, E; Dulery, BD; Haegele, KD |
| Journal | Drug Metabolism and Disposition |
| Volume | 22 |
| Issue | 5 |
| Page Numbers | 738-749 |
| Abstract | Mofegiline or MDL 72,974A ((E)-4-fluoro-beta-fluoromethylene benzene butanamine hydrochloride) is a selective enzyme-activated irreversible inhibitor of monoamine oxidase B, which is under development for use in the treatment of Parkinson's disease. Male beagle dogs were given single p.o. (20 mg/kg) and i.v. (5 mg/kg) doses of [14C]-Mofegiline. Total radioactivity excreted in urine and feces over 96 hr was, respectively, 75.5 +/- 3.8 and 6.3 +/- 3.4% of the dose after p.o. and 67.9 +/- 0.5 and 3.9 +/- 2.4% after i.v. administration. Unchanged drug in urine represented 3% of the dose after po and less than 1% after i.v. administration. Mofegiline was thus extensively metabolized in dogs, and urinary excretion was the major route of elimination of metabolites. HPLC, with on-line radioactivity detection, showed the presence of four major peaks (M1, M2, M3, and M4), representing respectively 50, 9, 5, and 0.5% of the administered dose excreted in 0-24 hr urine. TSP-LC-MS, FAB-MS, and NMR spectra of the purified metabolites were obtained. M1, the major metabolite in dogs, was shown to have undergone defluorination of the beta-fluoromethylene moiety, and one carbon addition. Its structure was confirmed to be a cyclic carbamate. M2 was a N-carbamoyl O-beta-D-glucuronide conjugate of parent drug. The formation of M1 and M2 is likely to involve initial reversible addition of CO2 to the primary amine function. M3 was a N-succinyl conjugate of the parent drug. M4 had also undergone defluorination to yield a urea adduct of an unsaturated alpha, beta aldehyde. Structures of M1 and M3 were further confirmed by comparing their MS and NMR spectra with those of authentic reference compounds. TSP-LC-MS ion chromatograms of human urine, obtained from two male volunteers after p.o. administration of 24 mg of drug, showed selected molecular ion peaks with the same retention time as the metabolites identified in dogs. In humans, these common metabolites represented a similar percentage of the administered dose to that in dogs. The present study demonstrates that NMR, TSP-LC-MS are complementary analytical techniques, which allow structural identification of unhydrolyzed drug conjugates. The formation of carbamates of amine-containing drugs may be more common than previously reported. |
| Pmid | 7835226 |
| Wosid | WOS:A1994PJ51300012 |
| Url | https://www.proquest.com/scholarly-journals/novel-carbamate-metabolites-mofegiline-primary/docview/77724933/se-2?accountid=171501 |
| Is Certified Translation | No |
| Dupe Override | No |
| Comments | Scopus URL: https://www.scopus.com/inward/record.uri?eid=2-s2.0-0028146445&partnerID=40&md5=d918bc67356bcccdf998cd37c974a5d4 |
| Is Public | Yes |
| Language Text | English |
| Keyword | amine oxidase (flavin containing) isoenzyme b; carbamic acid derivative; dopamine; drug metabolite; mofegiline; monoamine oxidase inhibitor; animal experiment; article; drug metabolism; drug structure; drug synthesis; enzyme inhibition; enzyme specificity; enzyme substrate; fast atom bombardment mass spectrometry; feces analysis; human; human experiment; intravenous drug administration; male; nonhuman; normal human; nuclear magnetic resonance; oral drug administration; parkinson disease; priority journal; radioactivity; urinary excretion; Administration, Oral; Allyl Compounds; Animal; Biotransformation; Butylamines; Carbamates; Chromatography, Liquid; Dogs; Human; Injections, Intravenous; Magnetic Resonance Spectroscopy; Male; Methylation; Monoamine Oxidase Inhibitors; Spectrometry, Mass, Fast Atom Bombardment; Spectrum Analysis, Mass; Tissue Distribution |