1. Ranitidine consumption did not result in higher urinary excretion of N-nitrosodimethylamine (NDMA) compared to placebo.
2. High nitrite diet increased urinary excretion of NDMA.
Evidence Rating Level: 1 (Excellent)
In 2020, ranitidine, a histamine 2 receptor blocker widely used as heartburn treatment, was removed from market due to concern over amount of carcinogen N-nitrosodimethylamine (NDMA) found in certain lots. Aside from potential contamination during manufacturing, ranitidine can form NDMA in humans during the process of degradation, especially in the presence of nitrites. However, whether a substantial amount of NDMA is produced after consumption of ranitidine and a nitrite-rich meal has not been shown.
In this randomized controlled trial, 18 healthy adults aged 28-43 were fasted overnight and received either ranitidine (300mg) or placebo alongside a breakfast high or low in nitrite. The study was conducted in a clinical pharmacology unit in West Bend, Wisconsin, during the months of June and July of 2020. Participants who consumed nicotine-containing products, had significant past medical history, or had used any prescription of non-prescription medication within 14 days of screening were excluded. The primary outcome was 24hr urinary excretion of NDMA.
There was no statistically significant difference between ranitidine and placebo group in 24hr urinary excretion of NDMA with (paired difference -1.1ng, P=0.71) or without (0ng p-0.54) high-nitrite diet. Additionally, there were no difference in plasma NDMA level in ranitidine or placebo group. Although this was reassuring regarding the potential safety of ranitidine, this study was limited in its generalizability since it was not conducted with patients with gastric disease, whose stomach pH may result in slightly altered metabolism of ranitidine. Therefore, further studies with larger cohort, in patients with gastric disease, and with longer-term use of ranitidine is still necessary. Nonetheless, this study was significant in establishing more physiological parameters for future testing of NDMA formation from ranitidine or other medications.
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