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Escaping the cohort of concern: in vitro experimental evidence supports non-mutagenicity of N-nitroso-hydrochlorothiazide.
Gandhi, R D; Hickert, S; Hoevelmann, Y; Mee, C D; Schlingemann, J; Adams, A; Blanazs, A; Simon, S; Elloway, J; Rigger, L; Teasdale, A; Beaumont, C V; Wright, L; Doherty, A.
Afiliación
  • Gandhi RD; Safety Sciences, R&D, AstraZeneca, Cambridge, UK.
  • Hickert S; Merck KGaA, Darmstadt, Germany.
  • Hoevelmann Y; Merck KGaA, Darmstadt, Germany.
  • Mee CD; Gentronix Ltd. Alderley Park, Macclesfield, UK.
  • Schlingemann J; Merck KGaA, Darmstadt, Germany. joerg.schlingemann@merckgroup.com.
  • Adams A; Chemical Development, Pharmaceutical Technology & Development, Operations, AstraZeneca, Macclesfield, UK.
  • Blanazs A; Chemical Development, Pharmaceutical Technology & Development, Operations, AstraZeneca, Macclesfield, UK.
  • Simon S; Merck KGaA, Darmstadt, Germany.
  • Elloway J; Safety Sciences, R&D, AstraZeneca, Cambridge, UK.
  • Rigger L; Reference Materials R&D, Merck KGaA, Buchs, Switzerland.
  • Teasdale A; Chemical Development, Pharmaceutical Technology & Development, Operations, AstraZeneca, Macclesfield, UK.
  • Beaumont CV; Safety Sciences, R&D, AstraZeneca, Cambridge, UK.
  • Wright L; Safety Sciences, R&D, AstraZeneca, Macclesfield, UK.
  • Doherty A; Safety Sciences, R&D, AstraZeneca, Cambridge, UK.
Arch Toxicol ; 2024 Sep 11.
Article en En | MEDLINE | ID: mdl-39259282
ABSTRACT
In recent years, nitrosamine impurities in pharmaceuticals have been subject to intense regulatory scrutiny, with nitrosamine drug substance-related impurities (NDSRIs) treated as cohort of concern impurities, regardless of predicted mutagenic potential. Here, we describe a case study of the NDSRI N-nitroso-hydrochlorothiazide (NO-HCTZ), which was positive in the bacterial reverse mutation (Ames) test but is unstable under the test conditions, generating formaldehyde among other products. The mutagenic profile of NO-HCTZ was inconsistent with that expected of a mutagenic nitrosamine, exhibiting mutagenicity in the absence of metabolic activation, and instead aligned well with that of formaldehyde. To assess further, a modified Ames system including glutathione (3.3 mg/plate) to remove formaldehyde was developed. Strains used were S. typhimurium TA98, TA100, TA1535, and TA1537, and E. coli WP2 uvrA/pKM101. In this system, formaldehyde levels were considerably lower, with a concomitant increase in levels of S-(hydroxymethyl)glutathione (the adduct formed between glutathione and formaldehyde). Upon retesting NO-HCTZ in the modified system (1.6-5000 µg/plate), a clear decrease in the mutagenic response was observed in the strains in which NO-HCTZ was mutagenic in the original system (TA98, TA100, and WP2 uvrA/pKM101), indicating that formaldehyde drives the response, not NO-HCTZ. In strain TA1535, an increase in revertant colonies was observed in the modified system, likely due to a thiatriazine degradation product formed from NO-HCTZ under Ames test conditions. Overall, these data support a non-mutagenic designation for NO-HCTZ and demonstrate the value of further investigation when a positive Ames result does not align with the expected profile.
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Idioma: En Revista: Arch Toxicol Año: 2024 Tipo del documento: Article País de afiliación: Reino Unido Pais de publicación: Alemania
Texto completo
Añadir a Mi BVS
Imprimir
XML
PubMed Links
Buscar en Google

Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Idioma: En Revista: Arch Toxicol Año: 2024 Tipo del documento: Article País de afiliación: Reino Unido Pais de publicación: Alemania