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Table of Contents
REVIEW ARTICLE
Year : 2022  |  Volume : 27  |  Issue : 2  |  Page : 109-113

N-nitrosodimethylamine (NDMA) and some prescribed medicines: A mini-review


1 Department of Internal Medicine, Alex Ekwueme Federal Teaching Hospital, Abakaliki, Ebonyi State, Nigeria
2 Department of Medicine, Nnamdi Azikiwe University Teaching Hospital, Nnewi, Anambra State, Nigeria
3 Department of Medicine, Enugu State University Teaching Hospital, Enugu, Nigeria
4 Department of Medicine, University of Nigeria Teaching Hospital, Enugu, Nigeria

Date of Submission24-Apr-2021
Date of Decision16-May-2021
Date of Acceptance10-Jul-2021
Date of Web Publication3-Mar-2022

Correspondence Address:
Chidiebere V Ugwueze
Department of Internal Medicine, Alex Ekwueme Federal Teaching Hospital, Abakaliki, Ebonyi State.
Nigeria
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/ijmh.IJMH_15_21

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  Abstract 

Recently, there have been notices of drug recalls by different pharmaceutical companies. This is based on the finding of high level of N-nitrosodimethylamine (NDMA) in such medications. These medications are useful in the management of some diseases which affect a significant percentage of the population. It is therefore necessary to evaluate the chemical substance (NDMA), the sources, mechanisms, and the effects it can pose on the users of implicated medications. It is also important to consider the possible ways to avert the entry of NDMA into the medications. The substance, NDMA, has been found to be present as an impurity in high concentration in certain drugs, especially metformin slow release, valsartan and ranitidine. The approved healthy daily intake of NDMA by Food and Drug Administration (FDA) is about 96 ng. However, the concentrations of NDMA found in these drugs were exceptionally high which led to their recall. The high level of NDMA may arise from contamination, direct synthetic process, or from the degradation process of the medicine. Chromatography is the best detection modality of NDMA. The carcinogenic risk is the most feared effect of accumulated NDMA beyond the acceptable limit. On the basis of the frequent recalls of these medications, it is therefore imperative that pharmacists, pharmacologists, and physicians are acquainted with the sources of NDMA. This is in view of the serious risk it can pose to patients’ safety and quality of life. These concerns have given rise to this review article.

Keywords: Chromatography, metformin, NDMA, ranitidine, valsartan


How to cite this article:
Ugwueze CV, Ezeude CM, Abonyi CM, Nwatu CB, Ukwaja KN, Young EE. N-nitrosodimethylamine (NDMA) and some prescribed medicines: A mini-review. Int J Med Health Dev 2022;27:109-13

How to cite this URL:
Ugwueze CV, Ezeude CM, Abonyi CM, Nwatu CB, Ukwaja KN, Young EE. N-nitrosodimethylamine (NDMA) and some prescribed medicines: A mini-review. Int J Med Health Dev [serial online] 2022 [cited 2022 May 24];27:109-13. Available from: https://www.ijmhdev.com/text.asp?2022/27/2/109/339023




  Introduction Top


N-nitrosodimethylamine (NDMA) is a yellow-coloured, liquid compound with the chemical formula (CH3)2NNO or C2H6N2O.[1] It is also referred to as dimethylnitrosamine. NDMA has a molar mass of 74.08 g/mol, a boiling point of 153°C, and a density of 1 g/cm3.[2] Other nitrosamine impurities include N-nitrosodiethylamine (NDEA), N-nitrosoethylisopropylamine (NEIPA), N-nitrosodiisopropylamine (NDIPA), N-methyl-4-aminobutyric acid (NMBA), and N-nitrosodibutylamine (NDBA).[3]

The detection of NDMAs at levels beyond the acceptable limit has led to the recall of some of the regular medications used in treating some non-communicable diseases. The review article is focussed on the properties, sources, and health implications of NDMA and some of the recalled medicines.


  Diagram of ndma (Structural Formula) Top




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The central nitrogen atom is bound to two methyl groups and NO group with bond angles of 120°. The intra-atomic distances between N-N and N-O are 1.32 and 1.26 Å, respectively.[4]


  Sources Top


NDMA is a contaminant found in drinking water. This is due to its characteristic miscibility with water.[5] The substance can easily be leached into ground water.

It was initially used as rocket fuel and softeners for polymers, but currently restricted to research purposes due to the associated toxicity.[5] Industrial sources involve reactions of alkylamines with nitric and nitrous oxides.[6] Bradley et al.[7] reported that water treatment plants can also generate NDMA during chlorination of waste water and during the use of chloramines for disinfection.[8]

Recently, NDMA was detected as a contaminant in some pharmaceutical industrial plants. Some drugs such as ranitidine may also intrinsically undergo degradation, especially in poor storage conditions producing NDMA.[9]

The four steps involved in the formation of NDMA are: nucleophilic substitution by chloramines, oxidation, dehydration, and nitrosation.[10] Nitrosation is the rate-limiting step in the NDMA reaction process.[11]


  Metabolism of ndma Top


Human exposure to NDMA is mainly through the oral route.[5] The exposures can occur through ingestion of contaminated water, smoked meat, or fish which has a high content of nitrosamines, cigarette smoking, and use of some cosmetic products and beverages.[6],[12],[13] Exposures through inhalation and skin contact are limited.[6] After ingestion, the substance is rapidly absorbed from the intestines up to 90%.[14],[15] NDMA and metabolites are widely and rapidly distributed in the body in minutes.[16] NDMA undergoes biotransformation in the liver via the cytochrome P450 microsomal enzyme system that requires nicotinamide adenine dinucleotide phosphate and oxygen.[17] The reactive metabolite, methyldiazonium ion, is unstable and breaks down to form alkylating complexes.[17] Cytochrome P450 2E1 in the course of metabolizing NDMA also produces reactive oxygen species which are implicated in cancer pathogenesis.[18],[19] The lungs, kidneys, and esophagus are also involved in the metabolism of NDMA.[17]

Urine is one of the means by which NDMA is excreted. This was exemplified by an increase in the urinary excretion of NDMA after oral ingestion of ranitidine up to 400-folds.[20] Schistosomiasis also releases N-nitrosamines which are implicated in the causation of bladder cancer. This further buttresses the urinary excretion of nitrosamines.[20]


  Detection Methods Top


Chromatography is the main detection modality. Both gas and liquid chromatography methods are utilized.[21] Solid phase extraction can also be used.

High-performance liquid chromatography (HPLC)

The method has been applied to some recalled valsartan in Japan and it showed good linearity with the correlation coefficient of R2> 0.999.[22] The limit of detection was 0.0085 μg/mL. The recalled valsartan in Japan in 2018 was subjected to HPLC to ascertain the level of NDMA and the quantity ranged from 36 to 74 ppm in the drug substances and 3.1–5.3 μg per tablet, respectively.[23]

Another form of liquid chromatographic method referred to as liquid chromatography-high resolution mass spectrometry (LC-HRMS) is capable of detecting other nitrosamines.[3]

Gas chromatography–mass spectrometry (GC–MS)

It is an efficient analytical method for the detection of nitrosamines. The high sensitivity and low interference are the advantages noted. However, chemical interference is noted during the analysis of low molecular mass nitrosamines.[24] Due to the intrinsic thermal degradation effect of ranitidine, this method is not efficiently used for the detection of nitrosamines in batches of ranitidine tested.[25],[26]

Solid phase extraction method

This involves the use of a solid phase to adsorb nitrosamines when the original mixture such as water or a drug mixture is passed through it. The substances used as solid phase include coconut charcoal,[27] activated charcoal from other sources,[28] and silica.[29]


  Medications of Concern Top


The substance NDMA has been found to be present as an impurity in high concentration in certain drugs, especially metformin slow release, valsartan, and ranitidine. The approved healthy daily intake of NDMA by Food and Drug Administration (FDA) is about 96 ng daily.[30] However, the concentrations of NDMA found in these drugs were exceptionally high which led to their recall.

Metformin

This is one of the principal anti-diabetic drugs whose importance spans beyond its glucose-lowering capacity. It has been reported to have anti-neoplastic effect as well as modulatory effect on endothelial function in diabetic patients.[31],[32] The relevance of metformin in diabetes management has made the recall of the drug to have a far-reaching effect on diabetic patients who are taking the medication.

The slow release forms have been implicated. Pharmaceutical companies such as Marksan recalled Metformin ER tablets, 500 and 750 mg.[33] Sun Pharmaceuticals also recalled Metformin ER oral suspension 500 mg per 5 mL in September, 2020.[34]

How does NDMA arise in metformin? Dimethyl amine is a precursor of NDMA and is used in the production of metformin.[35] NDMA may therefore arise in the presence of nitrosating agent, which can be a contaminant in the synthetic process.[9] The emphasis of pharmaceutical regulatory agencies is to ensure that the concentration of NDMA does not exceed the daily tolerable level.

Valsartan

This is a potent angiotensin receptor blocker which has an anti-remodeling effect on the heart as well as anti-proteinuric function in the renal glomerulus.[36] Therefore, the drug is vital to cardiologists and nephrologists.

The presence of the contaminant, NDMA, has also led to the recall of some batches of valsartan in certain countries. The Food and Drug Administration announced in 2018 a recall of valsartan produced by some pharmaceuticals such as Zhejiang Huahais, Zhejiang T, and Hetero Labs in India.[37] Losartan produced by Torrent Pharmaceuticals was also recalled due to the detection of N-methylnitrosobutyric acid (NMBA), which is also one of the nitrosamine impurities.[3]

Pottegård et al.[38] reported no increase in overall cancer risk arising from exposure to NDMA-contaminated valsartan compared with participants exposed to NDMA-uncontaminated valsartan [hazard ratio (HR)=1.09, 95% confidence interval 0.85–1.41]. However, the colorectal and uterine cancer risks were increased with HRs of 1.46 and 1.81, respectively.[38] The study was a nationwide study carried out among 5150 Danish populations taking valsartan.

How does NDMA arise from valsartan? It is traceable to the synthetic process. Initially, tributyltin azide was used to produce tetrazole and xylene used as solvent. However, tributylin was later replaced with sodium azide as the latter gives higher yields.[9] Similarly, xylene was changed to dimethylformamide which can produce dimethylamine (DMA). The “N” component of NDMA was obtained from sodium nitrite, which was introduced to eliminate excess sodium azide.[9]

Ranitidine

The drug is one of the medications used for treating gastro-oesophageal reflux disease (GERD) and peptic ulcer. It inhibits secretion of peptic acid by inhibiting H2 histamine receptor. Ranitidine undergoes nitrosation.[10] Nitrosation is a reaction of amines with nitrite to form nitrosamines.

It was discovered that some batches of ranitidine contained unacceptably high levels of NDMA. Emery Pharma in April 2020 recalled Zantac, a brand of rantidine.[39] This was due to its ability to form NDMA by a degradation process.

A clinical trial NCT04397445 was designed to ascertain the urinary excretion of NDMA after ranitidine administration.[40] The finding is yet to be published.

How does NDMA arise in ranitidine? This astronomical level of NDMA was attributed to the intrinsic instability of ranitidine molecule at temperatures above 130°C, which was used in the analytical process. The use of another analytical method LC-HRMS led to the quantification of lower NDMA levels, although higher than the normal daily intake.[39]

Moreover, ranitidine is an unstable drug and can undergo self-degradation to form NDMA. The drug has the two components (amines and nitrite) required in the formation of NDMA.[9] Thus, in the presence of adequate heat, there is a faster degradation with increased formation of NDMA.[9]

The brands of ranitidine by Pharmascience and Ranbaxy Pharmaceuticals in Canada were also recalled because of the unacceptable levels of NDMA found in them.[41] Ranitidine of 150 mg strength was recalled. The malignancies associated with NDMA in ranitidine include: thyroid, testicular, colorectal, and hepatocellular cancers.[42],[43]


  Mechanism of Carcinogenesis by ndma Top


NDMA is classified as a probable carcinogen (group 2A carcinogen) in humans.[5],[44] The carcinogenic pathway of NDMA[45] includes the following:

  1. There is initial biotransformation by hepatic cytochrome P450 microsomal enzymes, mainly cytochrome P450 2E1 subtype.


  2. The outcome of the first step is the generation of methyldiazonium ion which is a highly reactive metabolite.


  3. The formation of DNA adducts is integral to carcinogenesis by NDMA molecule. Some of the vital DNA adducts formed are N7-methylguanine and O6-methylguanine, although the former represents about 65% of all the adducts. N7-methylguanine and O6-methylguanine may induce carcinogenesis by causing mispairing of purines and pyrimidines.[46]


It is important to note that NDMA can also cause non-cancer-related diseases including hemorrhagic stroke, hepatic decompensation, and even death, although these are rare.[47] Moreover, immunosuppression has been reported.[48]


  Conclusion Top


NDMA has long been shown from animal studies to have carcinogenic potential. The levels in some common drugs have become a source of concern to drug manufacturers, physicians, and patients. Since it is very imperative that no harm should be inflicted on patients, it is therefore vital to ensure adequate understanding of NDMA, its effect on humans, and its quantification in some common medications. Regular monitoring of NDMA levels is also crucial even at the post-marketing surveillance so as not to exceed the daily requirements. More extensive studies are still needed to determine the toxic effects of NDMA in human tissues.

Financial support and sponsorship

The authors received no funding for the study.

Conflicts of interest

The authors declare that they have no conflicts of interest to disclose.

Author contributions

C. V. U.—conceptualization, literature search, and writing of the manuscript; C. M. E., C. M. A., K. N. U.—literature search and analysis; C. B. N., E. E. Y.—literature search and editing of the script. All the authors have read and agreed to the final version of the manuscript.



 
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Introduction
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Metabolism of ndma
Detection Methods
Medications of C...
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