Ranitidine use, N-Nitrosodimethylamine (NDMA) production and variations in cancer diagnoses

Introduction: Ranitidine is a member of the H2-blocker class of medications, commonly used in the treatment gastroesophageal reflux and peptic ulcer disease. Recent laboratory analyses have demonstrated that ranitidine may yield the probable carcinogen, N-Nitrosodimethylamine (NDMA). Here, we characterized the kinetics of NDMA production from ranitidine under various simulated gastric conditions. Moreover, we conducted a cross-sectional epidemiologic analysis to evaluate potential associations between ranitidine use and various cancer presentations. Methods: The formation of NDMA in the presence of ranitidine was studied in a series of experiments conducted in simulated gastric fluid (SGF), while varying pH, nitrite concentration, and time of reaction. Chemical analyses of NDMA yield were performed by liquid chromatography-high resolution mass spectrometry per FDA guidelines on the detection of NDMA from ranitidine drug products. To evaluate potential associations between ranitidine use and cancer diagnoses, we conducted a cross-sectional analysis among a population of oncology patients, following institutional review board approval. Analyses were limited to those reporting use of ranitidine or an active comparator (i.e. proton-pump inhibitor [PPI] or other H2-blocker) to partially mitigate potential confounding. Multivariable logistic regression was employed to identify associations between ranitidine and certain cancers, adjusted for age, sex, race, ethnicity, and body-mass index. Results: Increasing sodium nitrite concentrations in SGF at pH 1.2 were associated with increasing NDMA yield. At a pH of 2.5, previously identified as the optimal reaction condition, samples collected at incubation times of 1, 2 and 4 hours (approximating typical gastric emptying conditions) showed a continued increase in NDMA over time. Notably, the reaction trajectory suggests NDMA may have continued to form beyond the last observed timepoint of 4 hours. On cross-sectional analysis of an oncology population, use of ranitidine (versus active comparators) was associated with increased odds of presenting with cancers of the breast (OR=1.58; 95%CI: 1.23-2.01) as compared to presentation with another cancer. Similar positive associations were observed for cancers of the thyroid (OR=1.89; 95%CI: 1.18-2.92), bladder (OR=1.58; 95%CI: 1.10-2.21), and prostate (OR=1.80; 95%CI: 1.34-2.39). Conversely, ranitidine was inversely associated with cancers of the colorectum (OR=0.48; 95%CI: 0.30-0.74) and brain (OR=0.56; 95%CI: 0.33-0.89). Conclusion: Under simulated gastric conditions, ranitidine yields increasing amounts of NDMA over time (up to, and likely beyond 4 hours) and with increasing concentrations of sodium nitrite. In addition, among a cohort of cancer patients reporting use of H2-blockers or PPIs at the time of diagnosis, we found an association between ranitidine use and cancers of the breast, thyroid, bladder and prostate. We further observed unexplained inverse associations with cancers of the brain and colorectum. These associations reflect the odds of presenting with different cancers exclusively among an oncology population, and do not directly represent risk in a general population (as there were no cancer-free individuals in this study). Moreover, these exploratory analyses are to be viewed as hypothesis generating and should prompt analyses of larger cohorts with longer follow-up.