Mass spectral identification of the metabolites of alpha,alpha-dimethyl-4-(alpha,alpha,beta,beta-tetrafluorophenethyl)-benzylamine (MK-251), a novel antiarrhythmic agent, in various species.
The identification of a number of metabolites of the novel antiarrhythmic agent, alpha,alpha-dimethyl-4-(alpha,alpha,beta,beta-tetrafluorophenethyl)benzylamine (MK-251), is presented. The compound is extensively metabolized by dog, monkey, baboon and man. Similar metabolic profiles were obtained for all species. Isolation and purification were accomplished by solvent extraction and chromatographic (column, gas and thin-layer) procedures. Gas chromatography, derivatization, infrared, nuclear magnetic resonance and particularly combined gas chromatography low and high resolution mass spectrometry techniques were employed to characterize the metabolites. The major urinary and plasma metabolites were identified as 2-[4-(alpha,alpha,beta,beta-tetrafluorophenethyl)phenyl]-2-propanol and its glucuronide conjugate. Other metabolites characterized were: the N-glucuronide of MK-251; 2-[4-(alpha,alpha,beta,beta-tetrafluorophenethyl)phenyl]propene; 2-nitro-2-[4-)alpha,alpha,beta,beta-tetrafluorophenethyl)phenyl]propane; alpha,alpha-dimethyl-4(alpha,alpha,beta,beta-tetrafluorophenethyl)benzyl methyl ether; and 4-(alpha,alpha,beta,beta-tetrafluorophenethyl)acetophenone. The 0-methyl ether metabolite represents the first instance of in vivo alkylation of a tertiary alcohol. Tentative identification was made for the N-hydroxy analog of MK-251 and for the glycol analog of 2-[4-(alpha,alpha,beta,beta-tetrafluorophenethyl)phenyl]-2-propanol. The observed pharmacological response appears to result mainly from MK-251 and not from the four metabolites.
D000588:Amines / Q000032:analysis*; D000818:Animals; D000889:Anti-Arrhythmia Agents / Q000032:analysis*; D001596:Benzylamines / Q000032:analysis* / Q000097:blood / Q000652:urine; D055598:Chemical Phenomena; D002621:Chemistry; D002849:Chromatography, Gas; D004285:Dogs; D005260:Female; D000882:Haplorhini; D006801:Humans; D006845:Hydrocarbons, Fluorinated / Q000032:analysis* / Q000097:blood / Q000652:urine; D008253:Macaca mulatta; D008297:Male; D013058:Mass Spectrometry; D010215:Papio; D013055:Spectrophotometry, Infrared
D000588:Amines; D000889:Anti-Arrhythmia Agents; D001596:Benzylamines; D006845:Hydrocarbons, Fluorinated