In Vitro Analysis Of N-Nitrosodimethylamine (Ndma) Formation From Ranitidine Under Simulated Gastrointestinal Conditions (Vol 4, E2118253, 2021)

IMPORTANCE A publication reported that N-nitrosodimethylamine (NDMA), a probable human carcinogen, was formed when ranitidine and nitrite were added to simulated gastric fluid. However, the nitrite concentrations used were greater than the range detected in acidic gastric fluid in prior clinical studies.OBJECTIVE To characterize NDMA formation following the addition of ranitidine to simulated gastric fluid using combinations of fluid volume, pH levels, and nitrite concentrations, including physiologic levels.DESIGN, SETTING, AND PARTICIPANTS One 150-mg ranitidine tablet was added to 50 or 250 mL of simulated gastric fluid with a range of nitrite concentrations from the upper range of physiologic (100 mu mol/L) to higher concentrations (10 000 mu mol/L) with a range of pH levels. NDMA amounts were assessed with a liquid chromatography-mass spectrometry method.MAIN OUTCOMES AND MEASURES NDMA detected in simulated gastric fluid 2 hours after adding ranitidine.RESULTS At a supraphysiologic nitrite concentration (ie, 10 000 mu mol/L), the mean (SD) amount of NDMA detected in 50 mL simulated gastric fluid 2 hours after adding ranitidine increased from 222 (12) ng at pH 5 to 11 822 (434) ng at pH 1.2. Subsequent experiments with 50 mL of simulated gastric fluid at pH 1.2 with no added nitrite detected a mean (SD) of 22 (2) ng of NDMA, which is the background amount present in the ranitidine tablets. Similarly, at the upper range of physiologic nitrite (ie, 100 mu mol/L) or at nitrite concentrations as much as 50-fold greater (1000 or 5000 mu mol/L) only background mean (SD) amounts of NDMA were observed (21 [3] ng, 24 [2] ng, or 24 [3] ng, respectively). With 250 mL of simulated gastric fluid, no NDMA was detected at the upper physiologic range (100 mu mol/L) or 10-fold physiologic (1000 mu mol/L) nitrite concentrations, while NDMA was detected (mean [SD] level, 7353 [183] ng) at a 50-fold physiologic nitrite concentration (5000 mu mol/L).CONCLUSIONS AND RELEVANCE In this in vitro study of ranitidine tablets added to simulated gastric fluid with different nitrite concentrations, ranitidine conversion to NDMA was not detected until nitrite was 5000 mu mol/L, which is 50-fold greater than the upper range of physiologic gastric nitrite concentrations at acidic pH. These findings suggest that ranitidine is not converted to NDMA in gastric fluid at physiologic conditions.