Drug interactions I: detection of inorganic nitrite in organic nitrate esters under acidic conditions simulating the human stomach.
Both unformulated (bulk) and formulated (drugs) organic nitrate esters (isosorbide dinitrate, nitroglycerin, and pentaerythritol tetranitrate) were studied in the presence and absence of hydrochloric acid to determine if they could be sources of nitrite (and therefore lead to nitrosamine formation) under acidic conditions similar to those found in the stomach. The presence and generation of nitrite ion was detected by a modification of the Griess reaction. Bulk isosorbide dinitrate and nitroglycerin were found to be contaminated with 13.8-121.4 mumoles of inorganic nitrite per mole of nitrate ester. In addition, in the presence of hydrochloric acid, these preparations generated 0.52-1.18 mumoles of inorganic nitrite/mole of nitrate ester/min. Unformulated nitroglycerin generated nitrite at a rate roughly twice that of isosorbide dinitrate. In contrast, no evidence for nitrite contamination or generation by pentaerythritol tetranitrate was found. Tablets and capsules of isosorbide dinitrate contained approximately 27-216 mumoles of nitrite/mole of nitrate ester and, in the presence of hydrochloric acid, generated an average of 0.55 mumole nitrite/min. For isosorbide dinitrate, this rate was similar for bulk and formulated drug. In comparison to isosorbide dinitrate, the amount of nitrite initially present in tablets and capsules of nitroglycerin varied more widely (approximately 25-2290 mumoles nitrite/mole of nitrate ester), and in this case nitrite was generated at higher rates than unformulated drug averaging approximately 4.7 mumoles nitrite/mole of nitrate ester/min. Contrary to a literature report, we found that nitrate ion is not reduced to nitrite by hydrochloric acid (pH 1-3).(ABSTRACT TRUNCATED AT 250 WORDS)
D002626:Chemistry, Pharmaceutical; D004340:Drug Contamination; D005753:Gastric Mucosa / Q000378:metabolism*; D006801:Humans; D006863:Hydrogen-Ion Concentration; D009566:Nitrates / Q000032:analysis*; D009573:Nitrites / Q000032:analysis*; D005996:Nitroglycerin; D012997:Solvents; D013997:Time Factors; D014665:Vasodilator Agents / Q000032:analysis
D009566:Nitrates; D009573:Nitrites; D012997:Solvents; D014665:Vasodilator Agents; D005996:Nitroglycerin