Drug Interactions I: Detection of Inorganic Nitrite in Organic Nitrate Esters Under Acidic Conditions Simulating the Human Stomach

Abstract

□ 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 μmoles of inorganic nitrite per mole of nitrate ester. In addition, in the presence of hydrochloric acid, these preparations generated 0.52-1.18 μmoles 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 ~27–216 μιmoles of nitrite/mole of nitrate ester and, in the presence of hydrochloric acid, generated an average of 0.55 μmole 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 (~25–2290 μmoles nitrite/mole of nitrate ester), and in this case nitrite was generated at higher rates than unformulated drug averaging ~4.7 μmoles nitrite/mole of nitrate ester/min. Contrary to a literature report, we found that nitrate ion is not reduced to nitrite by hydrochloric acid (pH1–3). These data suggest that the continuous production of nitrite ion from isosorbide dinitrate and nitroglycerin is due to the hydrolysis of nitrite ester impurities, a reaction known to be strongly catalyzed by the chloride ion. Although the generation of inorganic nitrite from organic nitrate esters is of interest, the low levels of nitrite produced are unlikely to lead to intragastric nitrosamine formation.