The Landscape of Potential Small and Drug Substance Related Nitrosamines in Pharmaceuticals

Journal of Pharmaceutical Sciences, Год журнала: 2022, Номер 112(5), С. 1287 - 1304

Опубликована: Ноя. 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.

Язык: Английский

---

Risk assessment of N‐nitrosamines in food

EFSA Journal, Год журнала: 2023, Номер 21(3)

Опубликована: Март 1, 2023

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

Язык: Английский

---

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

Regulatory Toxicology and Pharmacology, Год журнала: 2024, Номер 150, С. 105640 - 105640

Опубликована: Май 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.

Язык: Английский

---

Mechanisms of Nitrosamine Mutagenicity and Their Relationship to Rodent Carcinogenic Potency

Chemical Research in Toxicology, Год журнала: 2024, Номер 37(2), С. 181 - 198

Опубликована: Фев. 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,

Язык: Английский

---

Quantum Chemical Evaluation and QSAR Modeling of N-Nitrosamine Carcinogenicity

Chemical Research in Toxicology, Год журнала: 2025, Номер unknown

Опубликована: Фев. 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.

Язык: Английский

---

What Makes a Potent Nitrosamine? Statistical Validation of Expert-Derived Structure–Activity Relationships

Chemical Research in Toxicology, Год журнала: 2022, Номер 35(11), С. 1997 - 2013

Опубликована: Окт. 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.

Язык: Английский

---

Regulatory Experiences with Root Causes and Risk Factors for Nitrosamine Impurities in Pharmaceuticals

Journal of Pharmaceutical Sciences, Год журнала: 2023, Номер 112(5), С. 1166 - 1182

Опубликована: Янв. 1, 2023

Язык: Английский

---

DNA Alkylation Damage by Nitrosamines and Relevant DNA Repair Pathways

International Journal of Molecular Sciences, Год журнала: 2023, Номер 24(5), С. 4684 - 4684

Опубликована: Фев. 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.

Язык: Английский

---

Association of Dietary Nitrate, Nitrite, and N-Nitroso Compounds Intake and Gastrointestinal Cancers: A Systematic Review and Meta-Analysis

Toxics, Год журнала: 2023, Номер 11(2), С. 190 - 190

Опубликована: Фев. 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.

Язык: Английский

---

Acceptable intakes (AIs) for 11 small molecule N-nitrosamines (NAs)

Regulatory Toxicology and Pharmacology, Год журнала: 2023, Номер 142, С. 105415 - 105415

Опубликована: Май 29, 2023

Low levels of N-nitrosamines (NAs) were detected in pharmaceuticals and, as a result, health authorities (HAs) have published acceptable intakes (AIs) to limit potential carcinogenic risk. The rationales behind the AIs not been provided understand process for selecting TD50 or read-across analog. In this manuscript we evaluated toxicity data eleven common NAs comprehensive and transparent consistent with ICH M7. This evaluation included substances which had datasets that robust, limited but sufficient, insufficient experimental animal carcinogenicity data. case robust sufficient information, calculated based on derived TD50s from most sensitive organ site. available structure activity relationships (SARs) applied categorical-based 1500 ng/day, 150 ng/day 18 ng/day; however additional (such biological computational modelling) could inform an alternative AI. approach advances methodology used derive NAs.

Язык: Английский

---