{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,20]],"date-time":"2026-10-20T17:26:02Z","timestamp":1792517162838,"version":"4.5.0"},"reference-count":64,"publisher":"Wiley","issue":"6-7","license":[{"start":{"date-parts":[[2024,8,24]],"date-time":"2024-08-24T00:00:00Z","timestamp":1724457600000},"content-version":"vor","delay-in-days":54,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Environ and Mol Mutagen"],"published-print":{"date-parts":[[2024,7]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:p>Evaluation and mitigation of the potential carcinogenic risks associated with nitrosamines in marketed pharmaceutical products are areas of interest for pharmaceutical companies and health authorities alike. Significant progress has been made to establish acceptable intake (AI) levels for <jats:italic>N<\/jats:italic>\u2010nitrosamine drug substance\u2010related impurities (NDSRIs) using SAR, however some compounds require experimental data to support derivation of a recommended AI. Many angiotensin\u2010converting enzyme inhibitors, identified by the suffix \u201cpril,\u201d have secondary amines that can potentially react to form nitrosamines. Here we consider a structural assessment and metabolism data, coupled with comprehensive in vitro and in vivo (mouse) genotoxicity testing to evaluate this particular class of nitrosamines. <jats:italic>N<\/jats:italic>\u2010nitroso ramipril and <jats:italic>N<\/jats:italic>\u2010nitroso quinapril, both of which are predicted to have inhibited nitrosamine bioactivation due to steric hinderance and branching at the \u03b1\u2010position were non\u2010genotoxic in the in vivo liver comet assay and non\u2010mutagenic in the in vivo Big Blue\u00ae mutation and duplex sequencing assays. Predicted metabolism along with in vitro metabolism data and quantum chemical calculations related to DNA interactions offer a molecular basis for the negative results observed in both in vitro and in vivo testing. These nitrosamines are concluded to be non\u2010mutagenic and non\u2010carcinogenic; therefore, they should be controlled according to ICH Q3B guidance. Furthermore, these results for <jats:italic>N<\/jats:italic>\u2010nitroso ramipril and <jats:italic>N<\/jats:italic>\u2010nitroso quinapril should be considered when evaluating the appropriate AI and control strategy for other structurally similar \u201cpril\u201d NDSRIs.<\/jats:p>","DOI":"10.1002\/em.22618","type":"journal-article","created":{"date-parts":[[2024,8,24]],"date-time":"2024-08-24T07:44:38Z","timestamp":1724485478000},"page":"203-221","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":20,"title":["Evaluation of the nitrosamine impurities of <scp>ACE<\/scp> inhibitors using computational, in vitro, and in vivo methods demonstrate no genotoxic potential"],"prefix":"10.1002","volume":"65","author":[{"given":"Jennifer","family":"Cheung","sequence":"first","affiliation":[{"name":"Pfizer Research, Development, and Medical  Groton Connecticut USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Krista","family":"Dobo","sequence":"additional","affiliation":[{"name":"Pfizer Research, Development, and Medical  Groton Connecticut USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0169-4078","authenticated-orcid":false,"given":"Shaofei","family":"Zhang","sequence":"additional","affiliation":[{"name":"Pfizer Research, Development, and Medical  Groton Connecticut USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Raphael","family":"Nudelman","sequence":"additional","affiliation":[{"name":"Teva Pharmaceutical Industries  Tel Aviv Israel"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Friedemann","family":"Schmidt","sequence":"additional","affiliation":[{"name":"Sanofi, R&amp;D Preclinical Safety  Frankfurt Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jan","family":"Wenzel","sequence":"additional","affiliation":[{"name":"Sanofi, R&amp;D Preclinical Safety  Frankfurt Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andreas","family":"Czich","sequence":"additional","affiliation":[{"name":"Sanofi, R&amp;D Preclinical Safety  Frankfurt Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maik","family":"Schuler","sequence":"additional","affiliation":[{"name":"Pfizer Research, Development, and Medical  Groton Connecticut USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2024,8,24]]},"reference":[{"key":"e_1_2_9_2_1","volume-title":"Physical chemistry","author":"Atkins P.","year":"2017"},{"key":"e_1_2_9_3_1","doi-asserted-by":"publisher","DOI":"10.1146\/annurev-biochem-013118-111315"},{"key":"e_1_2_9_4_1","doi-asserted-by":"publisher","DOI":"10.1063\/1.464913"},{"key":"e_1_2_9_5_1","doi-asserted-by":"publisher","DOI":"10.1063\/1.464304"},{"key":"e_1_2_9_6_1","doi-asserted-by":"publisher","DOI":"10.1093\/carcin\/17.9.2029"},{"key":"e_1_2_9_7_1","doi-asserted-by":"publisher","DOI":"10.1093\/carcin\/8.11.1635"},{"key":"e_1_2_9_8_1","doi-asserted-by":"publisher","DOI":"10.1002\/ijc.2910270408"},{"key":"e_1_2_9_9_1","doi-asserted-by":"publisher","DOI":"10.1177\/106002809102500510"},{"key":"e_1_2_9_10_1","doi-asserted-by":"publisher","DOI":"10.1021\/bi301092c"},{"key":"e_1_2_9_11_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.comtox.2021.100186"},{"key":"e_1_2_9_12_1","doi-asserted-by":"publisher","DOI":"10.1021\/jm050529c"},{"key":"e_1_2_9_13_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ddtec.2012.11.001"},{"key":"e_1_2_9_14_1","doi-asserted-by":"publisher","DOI":"10.1021\/acs.jmedchem.7b01552"},{"key":"e_1_2_9_15_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.toxrep.2024.01.012"},{"key":"e_1_2_9_16_1","doi-asserted-by":"publisher","DOI":"10.1021\/acs.chemrestox.1c00369"},{"key":"e_1_2_9_17_1","doi-asserted-by":"publisher","DOI":"10.1007\/BF00524152"},{"key":"e_1_2_9_18_1","unstructured":"EMA. 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