Drug interactions. II. Formation of nitrosamines from therapeutic drugs. Properties and kinetics of the formation of N-nitrosopropranolol from nitrite and the secondary amine propranolol hydrochloride.
In the presence of hydrochloric acid, nitrosamines may be generated from amines and nitrite. Most nitrosamines are carcinogens and many commonly used drugs contain potentially nitrosatable amine groups. Beta-adrenergic blockers, which have such amine groups, are widely prescribed and are often ingested for the lifetime of the patients, but their safety with respect to the intragastric formation of nitrosamines has not been established. The studies in this and the following report were designed to assess the potential risk posed by the endogenous formation of a nitrosamine in the stomach to individuals receiving longterm treatment with propranolol hydrochloride. The putative nitrosamine, N-nitrosopropranolol (NNP), was synthesized and its stability was examined under various experimental conditions. A high-pressure liquid chromatographic method was developed which detects a minimum of 7 X 10(-11) mol of NNP in the presence of large quantities of unreacted drug. Preparations of propranolol hydrochloride were found to contain several non-nitrosamine contaminants, which were removed before kinetic studies. At 37 degrees C, in solutions of HCl within the pH range found in the stomach, the optimum pH for the formation of NNP was 3. The yield of NNP increased linearly as incubation time and concentration of propranolol increased and exponentially as the concentration of nitrite was raised. Under optimal conditions in hydrochloric acid, the minimum concentration of nitrite required for the production of detectable amounts of NNP was 10(-5) M.
D055598:Chemical Phenomena; D002621:Chemistry; D004347:Drug Interactions; D008401:Gas Chromatography-Mass Spectrometry; D007700:Kinetics; D009682:Magnetic Resonance Spectroscopy; D013058:Mass Spectrometry; D009573:Nitrites; D009602:Nitrosamines; D011433:Propranolol / Q000031:analogs & derivatives*; D012977:Sodium Nitrite
D009573:Nitrites; D009602:Nitrosamines; C037601:N-nitrosopropranolol; D011433:Propranolol; D012977:Sodium Nitrite