In Vitro Analysis ofN-Nitrosodimethylamine (NDMA) Formation From Ranitidine Under Simulated Gastrointestinal Conditions

Abstract

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 μmol/L) to higher concentrations (10 000 μmol/L) with a range of pH levels. NDMA amounts were assessed with a liquid chromatography-mass spectrometry method. MAIN OUTCOMES AND MEASURESNDMA detected in simulated gastric fluid 2 hours after adding ranitidine.RESULTS At a supraphysiologic nitrite concentration (ie, 10 000 μmol/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 μmol/L) or at nitrite concentrations as much as 50-fold greater (1000 or 5000 μmol/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 μmol/L) or 10-fold physiologic (1000 μmol/L) nitrite concentrations, while NDMA was detected (mean [SD] level, 7353 [183] ng) at a 50-fold physiologic nitrite concentration (5000 μmol/L). CONCLUSIONS AND RELEVANCEIn 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 μmol/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.

New science, drug regulation, and emergent public health issues: The work of FDA’s division of applied regulatory science

“…The study found no evidence of increased NDMA content in participants’ urine or blood ( Figure 2 ) who were administered ranitidine ( 12 ). Additional in vitro investigations with simulated gastric fluid supported that ranitidine would not produce NDMA under physiologic conditions ( 13 ). With this information, FDA may consider allowing ranitidine products back on the market if they are manufactured to be stable with low, acceptable amounts of NDMA that do not increase over time.…”

Risk of N-Nitrosodimethylamine (NMDA) Formation With Ranitidine

“…To the Editor A recent Editorial accompanying our published clinical trial in JAMA and in vitro studies in JAMA Network Open provides comments on our work that found no evidence of ranitidine converting to N -nitrosodimethylamine (NDMA) in humans. The editorial suggests that chloramine in tap water could facilitate ranitidine conversion to NDMA in humans, citing a study that assessed NDMA in chloraminated tap water 24 hours after adding ranitidine.…”

“…The Editorial also suggests that consumption of a large, acidic, nitrite-rich meal by an obese person with a 2-L stomach volume could substantially increase NDMA production. However, this scenario is unlikely, as large meals are known to markedly increase pH, which substantially decreases the reactive form of nitrite . For additional context, in comparison with a fasting gastric pH of 1.2, which favors NDMA formation, approximately 70% of foods have a pH of 5 to 7, and 2% have a pH less than 3.…”

“…However, this scenario is unlikely, as large meals are known to markedly increase pH, which substantially decreases the reactive form of nitrite. 3 For additional context, in comparison with a fasting gastric pH of 1.2, which favors NDMA formation, approximately 70% of foods have a pH of 5 to 7, and 2% have a pH less than 3. Even cured meats with added nitrites have a pH of 5.5 to 6.5.…”

Errors in Figure Captions

“…In the Original Investigation “In Vitro Analysis of N -Nitrosodimethylamine (NDMA) Formation From Ranitidine Under Simulated Gastrointestinal Conditions,” 1 published June 28, 2021, there were errors in the captions for Figures 2, 3, and 4 and eFigure 3. The level of simulated gastric fluid in Figure 2 should have read 150 mg.…”