JPET xPharm- The Comprehensive Pharmacology Reference

Home Help [Feedback] [For Subscribers] [Archive] [Search] [Contents]
QUICK SEARCH:   [advanced]


     

This Article
Right arrow Full Text (PDF)
Right arrow Submit a response
Right arrow Alert me when this article is cited
Right arrow Alert me when eLetters are posted
Right arrow Alert me if a correction is posted
Services
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Citing Articles
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Raisfeld-Danse, I. H.
Right arrow Articles by Chen, J.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Raisfeld-Danse, I. H.
Right arrow Articles by Chen, J.

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

IH Raisfeld-Danse and J Chen

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.

Volume 225, Issue 3, pp. 713-719, 06/01/1983
Copyright © 1983 by American Society for Pharmacology and Experimental Therapeutics






Home Help [Feedback] [For Subscribers] [Archive] [Search] [Contents]
All ASPET Journals Molecular Pharmacology Pharmacological Reviews
Molecular Interventions Drug Metabolism and Disposition

Copyright © 1983 by the American Society for Pharmacology and Experimental Therapeutics.