Formation and reversibility of S-linked conjugates of N-(1-methyl-3,3-diphenylpropyl)isocyanate, an in vivo metabolite of N-(1-methyl-3,3-diphenylpropyl)formamaide, in rats.
The metabolic disposition of N-(1-methyl-3,3-diphenylpropyl) formamide was studied in rats. The water-soluble metabolites, N-acetyl-S-[N-(1-methyl-3,3-diphenylpropylcarbamoyl)]cysteine and S-[N-(1-methyl-3,3-diphenylpropylcarbamoyl)]glutathione, were identified in urine and bile, respectively, of rats doses with the secondary formamide. The structures of these metabolites were confirmed by comparison with synthetic standards and by using liquid chromatography mass spectrometry and fast atom bombardment mass spectrometry. Synthetic standards of these metabolites were obtained by reacting the N-(1-methyl-3,3-diphenylpropyl)isocyanate with glutathione or N-acetylcysteine in methanolic solutions. The isocyanate was obtained in high yield by reacting 1-methyl-3,3-diphenylpropylamine with trichloromethyl chloroformate. The S-linked conjugates released the isocyanate in mild alkali, but were stable under acidic conditions. The released isocyanate was characterized by comparison with the synthetic standard using GC/MS and HPLC. A mechanism is proposed for the base-catalyzed elimination of the isocyanate from the thiol conjugates.
Mutlib
A E
AE
Faculty of Pharmaceutical Sciences, University of British Columbia, Vancouver, Canada.
Talaat
R E
RE
Slatter
J G
JG
Abbott
F S
FS
D000111:Acetylcysteine / Q000378:metabolism; D000818:Animals; D001559:Benzhydryl Compounds / Q000138:chemical synthesis / Q000378:metabolism*; D001646:Bile / Q000737:chemistry / Q000378:metabolism*; D002853:Chromatography, Liquid; D003485:Cyanates / Q000138:chemical synthesis / Q000378:metabolism*; D005559:Formamides / Q000138:chemical synthesis / Q000378:metabolism*; D008401:Gas Chromatography-Mass Spectrometry; D005978:Glutathione / Q000378:metabolism; D006863:Hydrogen-Ion Concentration; D017953:Isocyanates; D009682:Magnetic Resonance Spectroscopy; D008297:Male; D013058:Mass Spectrometry; D051381:Rats; D011919:Rats, Inbred Strains
D001559:Benzhydryl Compounds; D003485:Cyanates; D005559:Formamides; D017953:Isocyanates; C067739:N-(1-methyl-3,3-diphenylpropyl)formamide; C067738:N-(1-methyl-3,3-diphenylpropyl)isocyanate; D005978:Glutathione; D000111:Acetylcysteine