Physiological disposition and metabolic fate of a new antiarrhythmic agent, alpha, alpha-dimethyl-4-(alpha, alpha, beta, beta-tetrafluorophenethyl) benzylamine in the rat, dog, monkey, baboon, and man.
The physiological disposition of a new orally active antiarrhythmic drug, alpha, alpha-dimethyl-4-(alpha, alpha, beta, beta-tetrafluorophenethyl)benzylamine (MK-251) was investigated in the rat, dog, rhesus monkey, baboon, and man. MK-251 was extensively absorbed after oral administration in all species. Fecal excretion was the major route of tracer elimination in the rat (70%) and dog (80%), whereas the monkey, baboon, and man excreted the majority of the dose via the urine (40-80%). MK-251 and/or its metabolites were widely distributed in rat tissues and exhibited tissue/plasma ratios greater than one in most instances. The lung, liver, and kidney possessed a high tissue affinity for drug and metabolites. The plasma and urinary profile of radioactivity indicated extensive metabolism of MK-251 in all species. Less than 5% of the plasma and urinary radioactivity was identified as unchanged drug. In spite of extensive metabolic transformations, a remarkable feature of this drug is its persistence in the plasma for long periods of time. This is thought to be due to tissue affinity. The metabolic pattern for MK-251 was essentially the same in all species. The major metabolites present in the plasma and the urine were identified as the carbinol analog of MK-251, 2-[4-(alpha, alpha, beta, beta-tetrafluorophenethyl)phenyl]-2-propanol (I), and its glucuronide conjugate. Other metabolites characterized in the urine and plasma were: the N-glucuronide of MK-251, 2-[4-(alpha, alpha, beta, beta-tetrafluorophenethyl)phenyl]propene (II), 2-nitro-2-[4-(alpha, alpha, beta, beta-tetrafluorophenethyl)phenyl]propane (III), alpha, alpha-dimethyl-4-(alpha, alpha, beta, beta-tetrafluorophenethyl)benzyl methyl ether (IV-1) and 4-(alpha, alpha, beta, beta-tetrafluorophenethyl), acetophenone (IV-2). Two minor urinary metabolites were tentatively identified as the N-hydroxy analog of MK-251 and the glycol analog of carbinol I. The in vivo formation of the methyl ether represents the first report of alkylation of a tertiary alcohol.
D000328:Adult; D000588:Amines / Q000378:metabolism*; D000818:Animals; D000889:Anti-Arrhythmia Agents / Q000097:blood / Q000378:metabolism* / Q000652:urine; D001596:Benzylamines / Q000097:blood / Q000378:metabolism* / Q000652:urine; D001667:Binding, Competitive; D001798:Blood Proteins / Q000378:metabolism; D002849:Chromatography, Gas; D002855:Chromatography, Thin Layer; D004285:Dogs; D005243:Feces / Q000032:analysis; D005260:Female; D006801:Humans; D006845:Hydrocarbons, Fluorinated / Q000097:blood / Q000378:metabolism* / Q000652:urine; D008253:Macaca mulatta; D008297:Male; D013058:Mass Spectrometry; D008875:Middle Aged; D009928:Organ Specificity; D010215:Papio; D011485:Protein Binding; D051381:Rats; D013045:Species Specificity; D013055:Spectrophotometry, Infrared
D000588:Amines; D000889:Anti-Arrhythmia Agents; D001596:Benzylamines; D001798:Blood Proteins; D006845:Hydrocarbons, Fluorinated