دورية أكاديمية
Metformin drugs under simulated gastric conditions can generate high nitrite-dependent levels of N-nitrosodimethylamine.
| العنوان: | Metformin drugs under simulated gastric conditions can generate high nitrite-dependent levels of N-nitrosodimethylamine. |
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| المؤلفون: | Georgescu GC; Victor Babes National Institute of Pathology, Bucharest, Romania.; Carol Davila University of Medicine and Pharmacy, Bucharest, Romania., Cretu-Stancu M; Dobrogen Tech, Ovidiu, CT, Romania. mircea.cta@gmail.com., Bucur O; Victor Babes National Institute of Pathology, Bucharest, Romania. octavian.bucur@genomica.gov.ro.; Genomics Research and Development Institute, Bucharest, Romania. octavian.bucur@genomica.gov.ro.; Viron Molecular Medicine Institute, Boston, MA, USA. octavian.bucur@genomica.gov.ro. |
| المصدر: | Scientific reports [Sci Rep] 2024 Jun 17; Vol. 14 (1), pp. 13910. Date of Electronic Publication: 2024 Jun 17. |
| نوع المنشور: | Journal Article |
| اللغة: | English |
| بيانات الدورية: | Publisher: Nature Publishing Group Country of Publication: England NLM ID: 101563288 Publication Model: Electronic Cited Medium: Internet ISSN: 2045-2322 (Electronic) Linking ISSN: 20452322 NLM ISO Abbreviation: Sci Rep Subsets: MEDLINE |
| أسماء مطبوعة: | Original Publication: London : Nature Publishing Group, copyright 2011- |
| مواضيع طبية MeSH: | Metformin*/analysis , Metformin*/chemistry , Dimethylnitrosamine*/analysis , Dimethylnitrosamine*/chemistry , Nitrites*/analysis, Drug Contamination ; Humans ; Chromatography, Liquid/methods ; Mass Spectrometry/methods ; Gastric Juice/chemistry |
| مستخلص: | N-nitrosodimethylamine (NDMA) and N-nitrosodiethylamine (NDEA), group 2A carcinogens, were detected in finished drug products, including metformin, ranitidine, sartans and other drugs which caused multiple recalls in the USA and Europe. Important studies also reported the formation of NDMA when ranitidine and nitrite were added to simulated gastric fluid. Our objective was to screen finished drug products from Europe and USA for nitrosamine impurities and investigate the formation of NDMA in metformin finished drug products when added to simulated gastric fluid. One dosage unit of 30 different commercially available drugs, including metformin, sartans, and ranitidine were tested for NDMA, NDEA, and dimethylformamide (DMF) impurities, using a liquid chromatography-mass spectrometry (LC-MS) method. Then, 6 metformin finished drug products were tested in stomach conditions for 2 h at 37 °C in a 100 mL solution with a pH of 2.5 and different nitrite concentrations (40, 10, 1, 0.1 mM) and tested for NDMA, and DMF using LC-MS. We measured NDMA, NDEA, and DMF in 30 finished drug products. NDMA and DMF were quantified for metformin drug products in simulated gastric fluid with different nitrite concentrations. None of the 30 drugs showed concerning levels of NDMA, NDEA, or DMF when tested as single tablets. However, when metformin tablets are added to simulated gastric fluid solutions with high nitrite concentrations (40 mM and 10 mM), NDMA can reach amounts of thousands of nanograms per tablet. At the closest concentration to physiologic conditions we used, 1 mM, NDMA is still present in the hundreds of nanograms in some metformin products. In this in vitro study, nitrite concentration had a very important effect on NDMA quantification in metformin tablets added to simulated gastric fluid. 1 mM nitrite caused an increase above the acceptable daily intake set by the U.S. Food and Drug Administration (FDA) for some of the metformin drugs. 10 mM, 40 mM nitrite solutions generated NDMA amounts exceeding by more than a hundred times the acceptable daily intake set by the FDA of 96 nanograms. These findings suggest that metformin can react with nitrite in gastric-like conditions and generate NDMA. Thus, patients taking metformin could be exposed to NDMA when high nitrite levels are present in their stomach, and we recommend including a statement within the Patient Package Inserts/Instructions for use. (© 2024. The Author(s).) |
| References: | N-Nitrosodimethylamine (CICADS 38, 2002), (accessed 15 April 2023). https://www.inchem.org/documents/cicads/cicads/cicad38.htm . Schulien, I. & Hasselblatt, P. Diethylnitrosamine-induced liver tumorigenesis in mice. Methods Cell Biol. 163, 137–152. https://doi.org/10.1016/bs.mcb.2020.08.006 (2021). (PMID: 10.1016/bs.mcb.2020.08.00633785162) Barnes, J. M. & Magee, P. N. Some toxic properties of dimethylnitrosamine. Br. J. Ind. Med. 11(3), 167–174 (1954). (PMID: 131821551037552) Parr, M. K. & Joseph, J. F. NDMA impurity in valsartan and other pharmaceutical products: Analytical methods for the determination of N-nitrosamines. J. Pharm. Biomed. Anal. 164, 536–549. https://doi.org/10.1016/j.jpba.2018.11.010 (2019). (PMID: 10.1016/j.jpba.2018.11.01030458387) List of Classifications—IARC Monographs on the Identification of carcinogenic hazards to humans, (accessed 11 December 2022). https://monographs.iarc.who.int/list-of-classifications/ . Commissioner O of the. FDA announces voluntary recall of several medicines containing valsartan following detection of an impurity. FDA. Published March 24, 2020, (accessed 11 December 2022). https://www.fda.gov/news-events/press-announcements/fda-announces-voluntary-recall-several-medicines-containing-valsartan-following-detection-impurity . Research C for DE and. Sandoz Inc. Issues Voluntary Nationwide Recall of One Lot of Losartan Potassium and Hydrochlorothiazide Due to the Detection of Trace Amounts of NDEA (N-Nitrosodiethylamine) Impurity Found in the Active Pharmaceutical Ingredient (API). U.S. Food and Drug Administration. Published July 22, 2019, (accessed 11 December 2022). https://www.fda.gov/safety/recalls-market-withdrawals-safety-alerts/sandoz-inc-issues-voluntary-nationwide-recall-one-lot-losartan-potassium-and-hydrochlorothiazide-due . ClinCalc DrugStats Database, (accessed 11 December 2022). https://clincalc.com/DrugStats/ . Ranitidine citizen petition, (accessed 11 December 2022) https://www.regulations.gov/document/FDA-2019-P-4281-0001 . Metformin Citizen Petition, (accessed 11 December 2022) https://www.regulations.gov/document/FDA-2020-P-0978-0001 . Research C for DE and. FDA Updates and Press Announcements on NDMA in Metformin. FDA. Published online August 12, 2021, (accessed 11 December 2022). https://www.fda.gov/drugs/drug-safety-and-availability/fda-updates-and-press-announcements-ndma-metformin . Commissioner O of the. FDA Requests Removal of All Ranitidine Products (Zantac) from the Market. FDA. Published April 2, 2020, (accessed 11 December 2022). https://www.fda.gov/news-events/press-announcements/fda-requests-removal-all-ranitidine-products-zantac-market . EMA. Ranitidine-containing medicinal products. European Medicines Agency. Published September 19, 2019, (accessed 11 December 2022). https://www.ema.europa.eu/en/medicines/human/referrals/ranitidine-containing-medicinal-products . EMA. Meeting highlights from the Committee for Medicinal Products Human Use (CHMP) 12–15 October 2020. European Medicines Agency. Published October 13, 2020, (accessed 11 December 2022). https://www.ema.europa.eu/en/news/meeting-highlights-committee-medicinal-products-human-use-chmp-12-15-october-2020 . PubChem. Ranitidine, (accessed 30 March 2024). https://pubchem.ncbi.nlm.nih.gov/compound/5039 . Golob, N., Peterlin, S., Grahek, R. & Roškar, R. NDMA formation due to active ingredient degradation and nitrite traces in drug product. J. Pharm. Sci. 112(5), 1277–1286. https://doi.org/10.1016/j.xphs.2023.03.007 (2023). (PMID: 10.1016/j.xphs.2023.03.00736925105) Wu Q, Kvitko E, Jessop A, et al. Analysis of Crowdsourced metformin tablets from individuals reveals widespread contamination with N-nitrosodimethylamine (NDMA) in the United States. Published online June 1, 2020:2020.05.22.20110635. https://doi.org/10.1101/2020.05.22.20110635. Control of Nitrosamine Impurities in Human Drugs Guidance for Industry FDA (accessed 11 December, 2022). https://www.fda.gov/media/141720/download. Braunstein, L. Z. et al. Analysis of ranitidine-associated N-nitrosodimethylamine production under simulated physiologic conditions. JAMA Netw Open. 4(1), e2034766. https://doi.org/10.1001/jamanetworkopen.2020.34766 (2021). (PMID: 10.1001/jamanetworkopen.2020.34766335125157846938) Sullivan GA. A comparison of traditional and alternative meat curing methods. :2. Deborah, J., Wexler, C.R. (ed). Metformin in the treatment of adults with type 2 diabetes mellitus. In: UpToDate. Wolters Kluwer. |
| معلومات مُعتمدة: | 31PFE/30.12.2021. Unitatea Executiva pentru Finantarea Invatamantului Superior, a Cercetarii, Dezvoltarii si Inovarii |
| فهرسة مساهمة: | Keywords: N-nitrosodiethylamine (NDEA); N-nitrosodimethylamine (NDMA); Acceptable intake (Ai); Active pharmaceutical ingredient-nitrite interaction; Internal standard; Metformin |
| المشرفين على المادة: | 9100L32L2N (Metformin) M43H21IO8R (Dimethylnitrosamine) 0 (Nitrites) |
| تواريخ الأحداث: | Date Created: 20240617 Date Completed: 20240618 Latest Revision: 20240711 |
| رمز التحديث: | 20240712 |
| مُعرف محوري في PubMed: | PMC11183255 |
| DOI: | 10.1038/s41598-024-63032-9 |
| PMID: | 38886399 |
| قاعدة البيانات: | MEDLINE |
Find this article in full text from Springer Verlag. 
Full Text Finder | تدمد: | 2045-2322 |
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| DOI: | 10.1038/s41598-024-63032-9 |