Possible nitrosodimethylamine formation in comparative in vitro nitrosation experiments with six different tetracycline antibiotics.
The hydrochlorides of tetracycline, minocycline, chlorotetracycline, anhydrochlorotetracycline, desmethylchlorotetracycline, oxytetracycline and doxycycline were reacted with sodium nitrite for two hours at 37 degrees C in aqueous buffer solutions at pH 2 and 4 under simulated stomach conditions. NDMA formation was detected from minocycline, doxycycline, oxytetracycline and anhydrochlorotetracycline by GLC and GLC-MS analysis. NDMA formation from minocycline and dodxycycline was blocked by ascorbic acid. The catalytic effect of sodium thiocyanate for NDMA formation from minocycline and nitrite was investigated. The different reactivities of the tested tetracyclines towards nitrite in acidic solutions (NDMA formation from minocycline, doxycycline, oxytetracycline and no NDMA formation from tetracycline, chlorotetracycline and desmethylchlorotetracycline) may be understood from stereochemical considerations. The failure of dealkylative nitrosation reactions in the latter tetracyclines is explained by the formation of intramolecular hydrogen bridge linkages between epidimethylamino groups at C-4 and OH groups at C-6. This hypothesis was proved by the observations of NDMA formation from anhydrochlortetracycline and sodium nitrite at pH 2.
D001205:Ascorbic Acid / Q000494:pharmacology; D055598:Chemical Phenomena; D002621:Chemistry; D004128:Dimethylnitrosamine / Q000032:analysis / Q000138:chemical synthesis* / Q000378:metabolism; D005753:Gastric Mucosa / Q000378:metabolism; D006801:Humans; D007536:Isomerism; D007700:Kinetics; D009602:Nitrosamines / Q000138:chemical synthesis*; D012907:Smoking / Q000378:metabolism; D013754:Tetracyclines / Q000378:metabolism
D009602:Nitrosamines; D013754:Tetracyclines; D004128:Dimethylnitrosamine; D001205:Ascorbic Acid