Mechanisms of Nitrosamine Mutagenicity and Their Relationship to Rodent Carcinogenic Potency

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

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Re‐Evaluating Acceptable Intake: A Comparative Study of N‐Nitrosomorpholine and N‐Nitroso Reboxetine Potency

Environmental and Molecular Mutagenesis, Journal Year: 2025, Volume and Issue: unknown

Published: March 22, 2025

ABSTRACT Establishing regulatory limits for Drug Substance‐Related Impurities (NDSRIs) is challenging due to the limited genotoxicity and carcinogenicity data available many of these impurities, often leading conservative approaches. In this study, we evaluated genotoxic potential two structurally related nitrosamines: N‐nitrosomorpholine (NMOR) N‐nitroso reboxetine. Compared well‐studied NMOR, there little toxicological information Currently, both compounds have an acceptable intake value 127 ng/day, based on a read‐across using NMOR. While tested positive in series vitro vivo assays, found that mutagenic reboxetine was significantly lower than The benchmark dose (BMD) analysis mutagenicity supports 24,000 ng/day Computational studies, carried out quantum‐mechanical CADRE program, were consistent with outcomes, suggesting at or above 1500 comparison prediction supported by computed reactivity hydroxylation step, greater steric hindrance alpha carbons, more facile proton transfer heterolysis toward aldehyde metabolite. presented work can be used refine improve Carcinogenic Potency Categorization Approach (CPCA). It also underscores importance collaboration between authorities, pharmaceutical industry, scientific researchers address risks while avoiding overestimation certain NDSRIs.

Language: Английский

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A systematic review on multipotent carcinogenic agent, N‐nitrosodiethylamine (NDEA), its major risk assessment, and precautions

Journal of Applied Toxicology, Journal Year: 2024, Volume and Issue: 44(8), P. 1108 - 1128

Published: Jan. 11, 2024

The International Agency for Research on Cancer has classified N-nitrosodiethylamine (NDEA) as a possible carcinogen and mutagenic substances, placing it in category 2A of compounds that are probably harmful to humans. It is found nature tobacco smoke, along with its precursors, also synthesized endogenously the human body. oral or parenteral administration minimal quantity NDEA results severe liver kidney organ damage. required bioactivation by CYP450 enzyme form DNA adduct alkylation mechanism. Thus, this directs oxidative stress injury cells due higher formation reactive oxygen species alters antioxidant system tissues, whereas free radical scavengers guard membranes from NDEA-directed many enzymes. This might be one reasons etiology cancer not limited certain target but can affect various organs systems. Although there approaches treatment NDEA-induced cancer, their therapeutic outcomes still very dismal. However, several precautions were considered taken during handling working NDEA, being best way lower down occurrence cancers. present review was designed enlighten general guidelines mechanism, alter line cause malignancy different parts animal body protective agents. revelation constant, unpredictable situations even common life may remarkably augment toxic potential through rise damage DNA.

Language: Английский

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N-nitrosamine impurity risk assessment in pharmaceuticals: Utilizing In vivo mutation relative potency comparison to establish an acceptable intake for NTTP

Regulatory Toxicology and Pharmacology, Journal Year: 2024, Volume and Issue: 152, P. 105681 - 105681

Published: July 26, 2024

The finding of N-nitrosodiethylamine (NDEA) and N-nitrosodimethylamine (NDMA) in marketed drugs has led to implementation risk assessment processes intended limit exposures the entire class N-nitrosamines. A critical component process is establishing exposure limits that are protective human health. One approach for novel N-nitrosamines conduct an vivo transgenic rodent (TGR) mutation study. Existing regulatory guidance on provides decision making criteria based interpreting TGR studies as overall positive or negative. However, point departure metrics, such benchmark dose (BMD), can be used define potency provide opportunity establish relevant limits. This achieved through relative comparison with model possessing robust mutagenicity carcinogenicity data. current work adds dataset by providing data N-nitrosopiperidine (NPIP). In was also generated a N-nitrosamine impurity identified sitagliptin-containing products, 7-nitroso-3-(trifluoromethyl)-5,6,7,8-tetrahydro-[1,2,4]triazolo-[4,3-a]pyrazine (NTTP). Using approach, we have demonstrated safety NTTP at above levels 1500 ng/day.

Language: Английский

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Nitrosamine acceptable intakes should consider variation in molecular weight: The implication of stoichiometric DNA damage

Regulatory Toxicology and Pharmacology, Journal Year: 2023, Volume and Issue: 145, P. 105505 - 105505

Published: Oct. 5, 2023

N-nitrosamines (NAs) are a class of compounds which many, especially the small dialkyl type, indirect acting DNA alkylating mutagens. Their presence in pharmaceuticals is subject to very strict acceptable daily intake (AI) limits, traditionally expressed on mass basis. Here we demonstrate that AIs not experimentally derived for specific compound, but via statistical extrapolation or read across suitable analog, should be molar scale corrected target substance's molecular weight. This would account mechanistic aspect each nitroso group can, at maximum, single mutation and number molecules per unit proportional weight (MW). In this regard have re-calculated EMA 18 ng/day regulatory default AI unknown nitrosamines propose revised 163 pmol/day. addition, provide MW-corrected those nitrosamine drug substance related impurities (NDSRIs) has pre-assigned by read-across. Regulatory acceptance fundamental scientific tenet allow one derive limits NDSRIs both meet health-protection goals technically feasible.

Language: Английский

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Risk-Based In Silico Mutagenic Assessment of Benzodiazepine Impurities Using Three QSAR Tools

Toxicology Reports, Journal Year: 2025, Volume and Issue: unknown, P. 102008 - 102008

Published: March 1, 2025

Language: Английский

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Nitrosamine Drug Substance-Related Impurities (NDSRIs) in Pharmaceuticals: Formation, Mitigation Strategies, and Emphasis on Mutagenicity Risks

Pharmaceutical Research, Journal Year: 2025, Volume and Issue: unknown

Published: April 23, 2025

Language: Английский

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HESI GTTC Ring Trial: Concordance between Ames and Rodent Carcinogenicity Outcomes for N-Nitrosamines (NAs) with Rat and Hamster Metabolic Conditions

Regulatory Toxicology and Pharmacology, Journal Year: 2025, Volume and Issue: unknown, P. 105835 - 105835

Published: April 1, 2025

A multi-sector study (i.e., Ring Trial) was designed to improve the in vitro detection of N-nitrosamine (NA)-associated mutagenicity by optimizing bacterial reverse mutation Ames) assay protocol and testing various conditions on sensitivity specificity for prediction rodent carcinogenicity. total 29 NAs 3 N-nitroso drug-like compounds from different structural classes carcinogenicity outcomes were tested (two independent laboratories per compound) across 5 strains using a 30-minute pre-incubation protocol. To evaluate impact metabolic activating systems (MASs), included use 10 or 30% liver S9 fractions prepared rats hamsters pretreated with inducers enzymatic activity. Results indicate that E. coli Salmonella typhimurium detecting single base pair mutations, coupled MASs containing hamster S9s most sensitive (90%) identifying are carcinogens. Regarding MAS combinations, highest rat (93%), but has low (45%), good laboratory agreement Ames calls (91%). DMSO water considered suitable solvents, except small-molecular weight alkyl NAs. These results will support harmonized NAs, giving high confidence negative result.

Language: Английский

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Development and Validation of a Sensitive LC-MS/MS Method for the Determination of N-Nitroso-Atenolol in Atenolol-Based Pharmaceuticals

Separations, Journal Year: 2025, Volume and Issue: 12(5), P. 122 - 122

Published: May 12, 2025

The recent detection of N-nitroso-atenolol, a mutagenic and potentially carcinogenic impurity in atenolol-based pharmaceuticals, has raised serious safety concerns emphasized the need for stringent analytical control. This study developed validated highly sensitive LC-MS/MS method quantifying N-nitroso-atenolol both active pharmaceutical ingredients (APIs) finished products. Quantification was carried out using multiple reaction monitoring (MRM) under positive-mode electrospray ionization (ESI). Separation performed on C18 reversed-phase column with gradient water methanol containing 0.1% formic acid. to meet specification limit 15 ng/mg, linear range 0.5–80 ng/mL, effectively covering 10–400% regulatory threshold. exhibited an excellent performance terms specificity, accuracy, precision, linearity, robustness. It achieved (LOD) 0.2 ng/mL (0.30 ng/mg) quantification (LOQ) 0.5 (0.75 ng/mg), alongside comprehensive uncertainty analysis expanded ±3.86 mg/kg. Application commercial atenolol products confirmed reliability practical utility method. approach offers critical tool manufacturers agencies monitor control ensuring compliance enhancing patient safety.

Language: Английский

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Nitrosamine Impurities in Pharmaceuticals: An Empirical Review of their Detection, Mechanisms, and Regulatory Approaches

Current Topics in Medicinal Chemistry, Journal Year: 2024, Volume and Issue: 24(6), P. 503 - 522

Published: Feb. 7, 2024

Abstract: Since their discovery in valsartan-containing drugs, nitrosamine impurities have emerged as a significant safety problem pharmaceutical products, prompting extensive recalls and suspensions. Valsartan, candesartan, irbesartan, olmesartan, other sartans been discovered to additional impurities, such N-nitroso-N-methyl-4-aminobutyric acid (NMBA), N-nitroso-Di-isopropyl amine (NDIPA), N-nitroso-Ethyl-Isopropyl (NEIPA), N-nitroso-Diethyl (NDEA). Concerns about drug grown response reports of contamination pharmaceuticals, pioglitazone, rifampin, rifapentine, varenicline. This review investigates the occurrence impact goods, well underlying causes. The discussion emphasizes significance comprehensive risk assessment mitigation approaches at various phases medication development manufacturing. link between amines is also investigated, with an emphasis on pH levels behaviour primary, secondary, tertiary, quaternary amines. Regulations defining standards for management, ICH Q3A-Q3E M7, are critical resolving impurity issues. Furthermore, Global Substance Registration System (GSRS) underlined being information sharing product industry. specifically focuses relationship ranitidine N-nitroso dimethyl (NDMA) context implications patient medicine supply. importance regulatory authorities discovering correcting highlighted order improve safety, quality, life expectancy. ongoing study attention nitrosamine-related repercussions increasing overall public health emphasized.

Language: Английский

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