Drug interactions. III. Formation of nitrosamines from therapeutic drugs. Formation, mutagenic properties and safety assessment of propranolol hydrochloride with respect to the intragastric formation of N-nitrosopropranolol under conditions found in patients.
In the preceding report, the kinetics of formation of N-nitrosopropranolol (NNP) from propranolol and inorganic nitrite were determined in solutions of hydrochloric acid over the range of pH similar to that found in the human stomach. In this communication, NNP formation was examined in human gastric juice and in the presence of organic nitrate ester vasodilator drugs. In comparison to HCl solutions, equivalent concentrations of propranolol and nitrite produced similar amounts of NNP in gastric juice; however, the yield increased as the pH was lowered and the kinetics of nitrosamine formation were different. Endogenous nitrite concentrations in 22 samples of human gastric juice were below the minimum concentration (10(-5) M) required for production of detectable levels of NNP. Maximal therapeutic dosages of propranolol (10(-2) M) incubated with isosorbide dinitrate (3,4-6.8 X 10(-3) M) or nitroglycerin (8.6 X 10(-4) M) also failed to produce NNP. However, NNP formed adventitiously during the concentration of aqueous and methylene chloride solutions that contained propranolol and organic nitrates, underscoring the importance of avoiding artifactual formation of nitrosamines. Furthermore, synthetic NNP was not mutagenic in either the Ames tester strains (TA92, TA98, TA100, TA1535, TA1537 and TA1538) or the hepatocyte-mediated mammalian cell mutagenesis assay. We conclude that NNP is unlikely to form in the stomach under conditions normally present in patients. Moreover, even if NNP formed under exceptional circumstances, this compound is unlikely to be a carcinogen. With respect to the potential formation of nitrosamines during drug dissolution in the stomach, long-term therapy with propranolol hydrochloride appears to be safe.
D001711:Biotransformation; D005750:Gastric Juice / Q000378:metabolism*; D006801:Humans; D007700:Kinetics; D009152:Mutagenicity Tests; D009153:Mutagens; D009154:Mutation; D009602:Nitrosamines / Q000378:metabolism* / Q000633:toxicity*; D011433:Propranolol / Q000031:analogs & derivatives* / Q000378:metabolism* / Q000633:toxicity; D012449:Safety; D012486:Salmonella typhimurium / Q000187:drug effects; D013861:Thiocyanates / Q000378:metabolism
D009153:Mutagens; D009602:Nitrosamines; D013861:Thiocyanates; C037601:N-nitrosopropranolol; D011433:Propranolol