Tale of Three N-Nitrosamines and the Variables Needed to Assess Their Carcinogenicity In Silico Incorporated into a Single Workflow DOI
Jakub Kostal, Adelina Voutchkova‐Kostal

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

Опубликована: Апрель 17, 2025

N-Nitrosamine impurities in pharmaceuticals present a considerable challenge for regulators and industry alike, where the absence of carcinogenic-potency studies has left gap that must be adequately filled to protect public health. In interim, this means balancing risk assessment with necessity continue research, development, supply pharmaceuticals. long term, we need cost-effective solution optimizes both. As if beholden Newton's Third Law, every crisis breeds an opportunity equal magnitude. Consequently, cross-industry consortia have been racing find by advancing our current science. Recent spotlight on silico tools, as fast increasingly reliable alternative vivo vitro testing. Because N-nitrosamine bioactivation lends itself uniquely quantum mechanics (QM) approaches, integration electronic-structure considerations emerged dominant approach. This signifies leap predictive toxicology, which has, much its existence, relied atomistic (quantitative) structure-activity relationships, i.e., (Q)SARs. Here validation integrated docking-QM approach within CADRE program demonstrate utility three different impurities, N-nitroso-7-monomethylamino-6-deoxytetracycline, N-nitroso-dabigatran etexilate, 1-methyl-4-nitrosopiperazine. We show combined strategy, considers bioavailability, transport, cytochrome P450 binding, reactivity, can leveraged supplement overly conservative Carcinogenic Potency Categorization Approach (CPCA) setting daily acceptable intake (AI) using defensible, highly mechanistic, quantitative drivers metabolism. To end, argue while N-nitroso-7-monomethylamino-6-deoxytetracycline 1-methyl-4-nitrosopiperazine are cohort-of-concern etexilate is not potent carcinogen (TD50 > 1.5 mg/kg/day), contrasting CPCA-derived AI. Lastly, discuss how tool broader landscape QM methods CPCA into single harmonized strategy carcinogenicity impurities.

Язык: Английский

Tale of Three N-Nitrosamines and the Variables Needed to Assess Their Carcinogenicity In Silico Incorporated into a Single Workflow DOI
Jakub Kostal, Adelina Voutchkova‐Kostal

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

Опубликована: Апрель 17, 2025

N-Nitrosamine impurities in pharmaceuticals present a considerable challenge for regulators and industry alike, where the absence of carcinogenic-potency studies has left gap that must be adequately filled to protect public health. In interim, this means balancing risk assessment with necessity continue research, development, supply pharmaceuticals. long term, we need cost-effective solution optimizes both. As if beholden Newton's Third Law, every crisis breeds an opportunity equal magnitude. Consequently, cross-industry consortia have been racing find by advancing our current science. Recent spotlight on silico tools, as fast increasingly reliable alternative vivo vitro testing. Because N-nitrosamine bioactivation lends itself uniquely quantum mechanics (QM) approaches, integration electronic-structure considerations emerged dominant approach. This signifies leap predictive toxicology, which has, much its existence, relied atomistic (quantitative) structure-activity relationships, i.e., (Q)SARs. Here validation integrated docking-QM approach within CADRE program demonstrate utility three different impurities, N-nitroso-7-monomethylamino-6-deoxytetracycline, N-nitroso-dabigatran etexilate, 1-methyl-4-nitrosopiperazine. We show combined strategy, considers bioavailability, transport, cytochrome P450 binding, reactivity, can leveraged supplement overly conservative Carcinogenic Potency Categorization Approach (CPCA) setting daily acceptable intake (AI) using defensible, highly mechanistic, quantitative drivers metabolism. To end, argue while N-nitroso-7-monomethylamino-6-deoxytetracycline 1-methyl-4-nitrosopiperazine are cohort-of-concern etexilate is not potent carcinogen (TD50 > 1.5 mg/kg/day), contrasting CPCA-derived AI. Lastly, discuss how tool broader landscape QM methods CPCA into single harmonized strategy carcinogenicity impurities.

Язык: Английский

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