Analysis of Ranitidine-Associated <i>N-</i>Nitrosodimethylamine Production Under Simulated Physiologic Conditions

Braunstein, Lior Z.; Kantor, Elizabeth D.; OʼConnell, Kelli; Hudspeth, Amber; Wu, Qian; Zenzola, Nicola; Light, David Y.

doi:10.1001/jamanetworkopen.2020.34766

Cited by 15 publications

(27 citation statements)

References 3 publications

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“…Furthermore, nonclinical mutagenicity studies with ranitidine from the early 1980s had used excessive nitrite concentrations, leading to questionable clinical relevance, as commented on by the authors of those studies. [35][36][37] In this study, as well as in the study by Gillatt et al, 10,34 the supraphysiologic nitrite concentrations used by in vitro studies 7,8 were compared with nitrite concentrations observed in physiological gastric fluid clinical studies. In addition, the interplay of reactive nitrite and pH was evaluated.…”

Section: Discussionmentioning

confidence: 97%

“… a NDMA detected may be from background amounts in the ranitidine tablets used in the study by Braunstein et al 7 …”

Section: Discussionmentioning

confidence: 98%

“…In contrast, Braunstein et al 7 ( Figure 4 ) detected the same amount of NDMA at 1000 μmol/L nitrite and 2500 μmol/L nitrite, while at 5000 μmol/L nitrite the NDMA amount increased. 13 Notably, Braunstein et al 7 did not report the background amounts of NDMA present in the ranitidine product they used in the study. Thus, the constant amount of NDMA they detected at the lower nitrite concentrations (ie, 1000 μmol/L and 2500 μmol/L) may be the result of background NDMA being present in the ranitidine tablets before being placed in simulated gastric fluid and not the result of ranitidine-to-NDMA conversion in simulated gastric fluid.…”

Section: Discussionmentioning

confidence: 99%

“…Review of the literature revealed that 25 μmol/L of nitrite (ie, 40-fold lower than the lowest concentration studied by Braunstein et al 7 ) had been considered the upper range of normal in the acidic fasting stomach based on published clinical studies. 10 However, that assessment was performed in 1985, and an updated evaluation of physiologic nitrite concentrations was warranted, with additional consideration of the potential effect of food; of medications, such as H2 blockers and proton pump inhibitors; and among specific patient groups.…”

Section: Introductionmentioning

confidence: 99%

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

Gao

Karfunkle

et al. 2021

JAMA Netw Open

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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.

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Section: Discussionmentioning

confidence: 97%

“… a NDMA detected may be from background amounts in the ranitidine tablets used in the study by Braunstein et al 7 …”

Section: Discussionmentioning

confidence: 98%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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

Gao

Karfunkle

et al. 2021

JAMA Netw Open

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“…Importantly, at higher nitrite concentrations, both Braunstein et al 10 and Gao et al 12 found much greater production of NDMA at lower pH levels, suggesting that little conversion of ranitidine to NDMA would occur in the intestines or the bloodstream. 10,11 In the report by Florian et al 13 in this issue of JAMA, the investigators report findings from a phase 1 randomized crossover trial that evaluated urinary NDMA excretion for 24 hours after consumption of ranitidine or placebo. Eighteen healthy volunteers (median age, 33 years; 50% women) fasted overnight, consumed ranitidine (300 mg) or placebo, and then immediately ate a breakfast that was lower or higher in nitrate/ nitrite, based on consumption of a diet with a noncuredmeats diet and a cured-meats diet.…”

mentioning

confidence: 93%

Ranitidine and Risk ofN-Nitrosodimethylamine (NDMA) Formation

White

Hernández

2021

JAMA

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The US Food and Drug Administration (FDA) limits the amount of the probable carcinogen N-nitrosodimethylamine (NDMA) in a daily dose of medication to 96 ng. 1 Chronic NDMA exposure has been shown to induce liver and lung cancer in animals, while high-dose acute NDMA poisoning can damage the liver and induce gastrointestinal and hepatic bleeding. 2 Since 2019, NDMA exceeding this amount was found in numerous lots of several medications-such as angiotensin receptor blockers, sustained-release metformin, and ranitidine-and led to widespread recalls of several products and concern among patients and clinicians. 3 On April 1, 2020, based on an ongoing investigation of NDMA in ranitidine, the FDA requested manufacturers of ranitidine to remove all over-the-counter and prescription ranitidine products from the market. 4 The FDA meticulously evaluated sources of NDMA and other nitrosamine contamination during the manufacturing process and established new procedures that manufacturers can take to prevent this issue from occurring in the future. By March 31, 2021, all manufacturers of chemically synthesized active pharmaceutical ingredients and finished pharmaceutical products that are FDA approved or pending approval had to conduct initial risk assessments for nitrosamine contamination. 5 However, the manufacturing facility is not the only place NDMA can be introduced into medications. Ranitidine forms NDMA as the product degrades on the store shelf and in the medicine cabinet, especially when exposed to heat and humidity. 6,7 According to a laboratory study from 2011, several dimethylamine-containing drugs bound to an electronrich moiety (such as ranitidine, doxylamine and chlorpheniramine, sumatriptan, nizatidine, diltiazem, and tetracycline) form NDMA when exposed to chloramine, a commonly used drinking water disinfectant. 8 Of these, ranitidine produced the highest amounts of NDMA by far. 8 These alternate production sources bypass the safety procedures just enacted by the FDA to prevent excessive NDMA exposure.Before the middle of May 2021, the available literature suggested that ranitidine could be a potential source of NDMA creation in the body. 9,10 In 2016, a small unblinded study by Zeng and Mitch 9 found more than 40 000 ng of NDMA in the urine of 10 people taking ranitidine. In January 2021, an in vitro human stomach simulation study by Braunstein et al 10 found that 947 ng and 320 000 ng of NDMA were created when 100 mL of 1000 μmol/L and 50 000 μmol/L sodium nitrite, respectively, were inter-

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Effect of Oral Ranitidine on Urinary Excretion ofN-Nitrosodimethylamine (NDMA)

Florian

Matta

DePalma

et al. 2021

JAMA

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IMPORTANCE In 2019, the US Food and Drug Administration (FDA) received a citizen petition indicating that ranitidine contained the probable human carcinogen N-nitrosodimethylamine (NDMA). In addition, the petitioner proposed that ranitidine could convert to NDMA in humans; however, this was primarily based on a small clinical study that detected an increase in urinary excretion of NDMA after oral ranitidine consumption.OBJECTIVE To evaluate the 24-hour urinary excretion of NDMA after oral administration of ranitidine compared with placebo. DESIGN, SETTING, AND PARTICIPANTS Randomized, double-blind, placebo-controlled, crossover clinical trial at a clinical pharmacology unit (West Bend, Wisconsin) conducted in 18 healthy participants. The study began in June 2020, and the end of participant follow-up was July 1, 2020.INTERVENTIONS Participants were randomized to 1 of 4 treatment sequences and over 4 periods received ranitidine (300 mg) and placebo (randomized order) with a noncured-meats diet and then a cured-meats diet. The cured-meats diet was designed to have higher nitrites, nitrates (nitrate-reducing bacteria can convert nitrates to nitrites), and NDMA. MAIN OUTCOME AND MEASURE Twenty-four-hour urinary excretion of NDMA.RESULTS Among 18 randomized participants (median age, 33.0 [interquartile range {IQR}, 28.3 to 42.8] years; 9 women [50%]; 7 White [39%], 11 African American [61%]; and 3 Hispanic or Latino ethnicity [17%]), 17 (94%) completed the trial. The median 24-hour NDMA urinary excretion values for ranitidine and placebo were 0.6 ng (IQR, 0 to 29.7) and 10.5 ng (IQR, 0 to 17.8), respectively, with a noncured-meats diet and 11.9 ng (IQR, 5.6 to 48.6) and 23.4 ng (IQR, 8.6 to 36.7), respectively, with a cured-meats diet. There was no statistically significant difference between ranitidine and placebo in 24-hour urinary excretion of NDMA with a noncured-meats diet (median of the paired differences, 0 [IQR, −6.9 to 0] ng; P = .54) or a cured-meats diet (median of the paired differences, −1.1 [IQR, −9.1 to 11.5] ng; P = .71). No drug-related serious adverse events were reported. CONCLUSIONS AND RELEVANCEIn this trial that included 18 healthy participants, oral ranitidine (300 mg), compared with placebo, did not significantly increase 24-hour urinary excretion of NDMA when participants consumed noncured-meats or cured-meats diets. The findings do not support that ranitidine is converted to NDMA in a general, healthy population.

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Analysis of Ranitidine-Associated N-Nitrosodimethylamine Production Under Simulated Physiologic Conditions

Cited by 15 publications

References 3 publications

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

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

Ranitidine and Risk ofN-Nitrosodimethylamine (NDMA) Formation

Effect of Oral Ranitidine on Urinary Excretion ofN-Nitrosodimethylamine (NDMA)

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