Nitrosamines crisis in pharmaceuticals − Insights on toxicological implications, root causes and risk assessment: A systematic review DOI Creative Commons

Hemanth P.R. Vikram,

Tegginamath Pramod Kumar,

Gunjan Kumar

et al.

Journal of Pharmaceutical Analysis, Journal Year: 2023, Volume and Issue: 14(5), P. 100919 - 100919

Published: Dec. 12, 2023

The presence of N-nitroso compounds, particularly N-nitrosamines, in pharmaceutical products has raised global safety concerns due to their significant genotoxic and mutagenic effects. This systematic review investigates toxicity active ingredients, drug products, excipients, along with novel analytical strategies for detection, root cause analysis, reformulation strategies, regulatory guidelines nitrosamines. emphasizes the molecular focusing on genotoxic, mutagenic, carcinogenic, other physiological Additionally, it addresses ongoing nitrosamine crisis, development nitrosamine-free importance sensitive detection methods precise risk evaluation. comprehensive overview will aid biologists, scientists, formulation scientists research sector, researchers involved management nitrosamine-induced promoting safer products.

Language: Английский

The Landscape of Potential Small and Drug Substance Related Nitrosamines in Pharmaceuticals DOI Creative Commons
Joerg Schlingemann, Michael J. Burns, David J. Ponting

et al.

Journal of Pharmaceutical Sciences, Journal Year: 2022, Volume and Issue: 112(5), P. 1287 - 1304

Published: Nov. 17, 2022

This article reports the outcome of an in silico analysis more than 12,000 small molecule drugs and drug impurities, identifying nitrosatable structures, assessing their potential to form nitrosamines under relevant conditions challenges determine compound-specific AIs based on data available or read-across approaches for these acceptance by health authorities. Our indicate that presence pharmaceuticals is likely prevalent originally expected. In total, 40.4 % analyzed APIs 29.6 API impurities are nitrosamine precursors. Most structures identified through our workflow could complex API-related nitrosamines, so-called substance related (NDSRIs), although we also found release well-known potent NDMA, NDEA, others. Due common structural motifs including secondary tertiary amine moieties, whole essential classes such as beta blockers ACE inhibitors at risk. To avoid risk shortages even complete loss therapeutic options, it will be well-established ICH M7 principles remain applicable industry regulatory authorities keep open communication not only about science but make sure there a good balance between benefit patients.

Language: Английский

Citations

77
Risk assessment of N‐nitrosamines in food DOI Creative Commons

Dieter Schrenk,

Margherita Bignami,

Laurent Bodin

et al.

EFSA Journal, Journal Year: 2023, Volume and Issue: 21(3)

Published: March 1, 2023

EFSA was asked for a scientific opinion on the risks to public health related presence of

Language: Английский

Citations

73
Determining recommended acceptable intake limits for N-nitrosamine impurities in pharmaceuticals: Development and application of the Carcinogenic Potency Categorization Approach (CPCA) DOI Creative Commons

Naomi L. Kruhlak,

Marianne Schmidt,

Roland Froetschl

et al.

Regulatory Toxicology and Pharmacology, Journal Year: 2024, Volume and Issue: 150, P. 105640 - 105640

Published: May 14, 2024

N-Nitrosamine impurities, including nitrosamine drug substance-related impurities (NDSRIs), have challenged pharmaceutical industry and regulators alike affected the global supply over past 5 years. Nitrosamines are a class of known carcinogens, but NDSRIs posed additional challenges as many lack empirical data to establish acceptable intake (AI) limits. Read-across analysis from surrogates has been used identify AI limits in some cases; however, this approach is limited by availability robustly-tested matching structural features NDSRIs, which usually contain diverse array functional groups. Furthermore, absence surrogate resulted conservative cases, posing practical for impurity control. Therefore, new framework determining recommended was urgently needed. Here, Carcinogenic Potency Categorization Approach (CPCA) its supporting scientific rationale presented. The CPCA rapidly-applied structure-activity relationship-based method that assigns 1 categories, each with corresponding limit, reflecting predicted carcinogenic potency. considers number distribution α-hydrogens at N-nitroso center other activating deactivating affect α-hydroxylation metabolic activation pathway carcinogenesis. adopted internationally several regulatory authorities simplified starting point determine nitrosamines without need compound-specific data.

Language: Английский

Citations

20
Mechanisms of Nitrosamine Mutagenicity and Their Relationship to Rodent Carcinogenic Potency DOI
David J. Snodin, Alejandra Trejo‐Martin, David J. Ponting

et al.

Chemical Research in Toxicology, Journal Year: 2024, Volume and Issue: 37(2), P. 181 - 198

Published: Feb. 5, 2024

A thorough literature review was undertaken to understand how the pathways of N-nitrosamine transformation relate mutagenic potential and carcinogenic potency in rodents. Empirical computational evidence indicates that a common radical intermediate is created by CYP-mediated hydrogen abstraction at α-carbon; it responsible for both activation, leading formation DNA-reactive diazonium species, deactivation denitrosation. There are competing sites CYP metabolism (e.g., β-carbon), other reactive species can form following initial bioactivation, although these alternative tend decrease rather than enhance potency. The activation pathway, oxidative dealkylation, reaction drug carbonyl byproduct, e.g., formaldehyde, does not contribute toxic properties N-nitrosamines. Nitric oxide (NO), side product denitrosation, similarly be discounted as an enhancer toxicity based on carcinogenicity data substances act NO-donors. However, all N-nitrosamines potent rodent carcinogens. In significant number cases, there overlap with non-N-nitrosamine carcinogens Cohort Concern (CoC; high-potency comprising aflatoxin-like-, N-nitroso-, alkyl-azoxy compounds), while devoid potential. this context, mutagenicity useful surrogate carcinogenicity, proposed ICH M7 (R2) (2023) guidance. Thus, safety assessment control medicines, important those complementary attributes mechanisms structure–activity relationships translate elevated versus which associated reduction in, or absence of,

Language: Английский

Citations

19
Quantum Chemical Evaluation and QSAR Modeling of N-Nitrosamine Carcinogenicity DOI
Sebastian Schieferdecker,

Esther Vock

Chemical Research in Toxicology, Journal Year: 2025, Volume and Issue: unknown

Published: Feb. 6, 2025

N-Nitrosamine compounds in pharmaceuticals are a major concern due to their carcinogenic potential. However, not all nitrosamines strong carcinogens, and understanding the structure-activity relationships of this compound group is challenge. The determination acceptable intake limits for determined by applying either simple potency categorization approach (CPCA) or read-across analysis from where experimental data exist. emergence structurally complex makes quantitative models desirable. Here, we present two-step modeling based on linear discriminant set quantum mechanical classical descriptors followed 3D-QSAR PLS regression model predict logTD50 nitrosamine compounds.

Language: Английский

Citations

2
What Makes a Potent Nitrosamine? Statistical Validation of Expert-Derived Structure–Activity Relationships DOI Creative Commons
Robert Thomas, Rachael E. Tennant,

Antonio Anax Falcão de Oliveira

et al.

Chemical Research in Toxicology, Journal Year: 2022, Volume and Issue: 35(11), P. 1997 - 2013

Published: Oct. 27, 2022

The discovery of carcinogenic nitrosamine impurities above the safe limits in pharmaceuticals has led to an urgent need develop methods for extending structure–activity relationship (SAR) analyses from relatively limited datasets, while level confidence required that SAR indicates there is significant value investigating effect individual substructural features a statistically robust manner. This challenging exercise perform on small dataset, since practice, compounds contain mixture different features, which may confound both expert and statistical quantitative (QSAR) methods. Isolating effects single structural feature made difficult due confounding other functionality as well issues relating determining significance cases concurrent tests large number potential variables with dataset; naïve QSAR model does not predict any be after correction multiple testing. We propose variation Bayesian linear regression estimate each simultaneously yet independently, taking into account combinations present dataset reducing impact testing, showing some have impact. method can used provide validation approaches differences potency between groupings nitrosamines. Structural lead highest lowest isolated using this method, novel assigned categories high accuracy.

Language: Английский

Citations

45
Regulatory Experiences with Root Causes and Risk Factors for Nitrosamine Impurities in Pharmaceuticals DOI Open Access

Stephen Horne,

Matthew D. Vera,

Laxma R. Nagavelli

et al.

Journal of Pharmaceutical Sciences, Journal Year: 2023, Volume and Issue: 112(5), P. 1166 - 1182

Published: Jan. 1, 2023

Language: Английский

Citations

40
Metabolism and DNA Adduct Formation of Tobacco-Specific N-Nitrosamines DOI Open Access
Yupeng Li, Stephen S. Hecht

International Journal of Molecular Sciences, Journal Year: 2022, Volume and Issue: 23(9), P. 5109 - 5109

Published: May 4, 2022

The tobacco-specific N-nitrosamines 4-(N-nitrosomethylamino)-1-(3-pyridyl)-1-butanone (NNK) and N′-nitrosonornicotine (NNN) always occur together exclusively in tobacco products or environments contaminated by smoke. They have been classified as “carcinogenic to humans” the International Agency for Research on Cancer. In 1998, we published a review of biochemistry, biology carcinogenicity nitrosamines. Over past 20 years, considerable progress has made our understanding mechanisms metabolism DNA adduct formation these two important carcinogens, along with their mutagenicity. this review, aim provide an update interactions NNK NNN.

Language: Английский

Citations

39
DNA Alkylation Damage by Nitrosamines and Relevant DNA Repair Pathways DOI Open Access
Jörg Fahrer, Markus Christmann

International Journal of Molecular Sciences, Journal Year: 2023, Volume and Issue: 24(5), P. 4684 - 4684

Published: Feb. 28, 2023

Nitrosamines occur widespread in food, drinking water, cosmetics, as well tobacco smoke and can arise endogenously. More recently, nitrosamines have been detected impurities various drugs. This is of particular concern are alkylating agents that genotoxic carcinogenic. We first summarize the current knowledge on different sources chemical nature with a focus relevant nitrosamines. Subsequently, we present major DNA alkylation adducts induced by upon their metabolic activation CYP450 monooxygenases. then describe repair pathways engaged adducts, which include base excision repair, direct damage reversal MGMT ALKBH, nucleotide repair. Their roles protection against carcinogenic effects highlighted. Finally, address translesion synthesis tolerance mechanism to adducts.

Language: Английский

Citations

39
Association of Dietary Nitrate, Nitrite, and N-Nitroso Compounds Intake and Gastrointestinal Cancers: A Systematic Review and Meta-Analysis DOI Creative Commons
Monireh Sadat Seyyedsalehi, Elham Mohebbi,

Fatemeh Tourang

et al.

Toxics, Journal Year: 2023, Volume and Issue: 11(2), P. 190 - 190

Published: Feb. 17, 2023

N-nitroso compounds (NOCs) are a class of chemical carcinogens found in various environmental sources such as food, drinking water, cigarette smoke, the work environment, and indoor air population. We conducted systematic review meta-analysis to investigate links between nitrate, nitrite, NOCs food water risk gastrointestinal (GI) cancers, including esophageal cancer (EC), gastric (GC), colorectal (CRC), pancreatic (PC). A search literature Scopus, PubMed, Google Scholar, Web Science, ScienceDirect, Embase was performed for studies on association GI cancers. Forest plots relative (RR) were constructed all sites intake sources. The random-effects model used assess heterogeneity studies. Forty articles included after removing duplicate irrelevant articles. indicated that high dose vs. low these significantly associated with overall nitrite (RR = 1.18, 95% CI 1.07–1.29), N-nitrosodimethylamine (NDMA) 1.32, 1.06–1.65). dietary increased GC 1.33, 1.02–1.73), EC 1.38, 1.01–1.89). Additionally, NDMA CRC 1.36, 1.18–1.58). This provides some evidence may be In particular, is linked risks CRC.

Language: Английский

Citations

38