{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,21]],"date-time":"2026-09-21T10:01:19Z","timestamp":1789984879586,"version":"4.0.1"},"reference-count":25,"publisher":"Wiley","issue":"1","license":[{"start":{"date-parts":[[2013,11,21]],"date-time":"2013-11-21T00:00:00Z","timestamp":1384992000000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Rapid Comm Mass Spectrometry"],"published-print":{"date-parts":[[2014,1,15]]},"abstract":"<jats:sec>\n                    <jats:title>RATIONALE<\/jats:title>\n                    <jats:p>\n                      Recent publications have reported that imatinib forms cyanide and methoxylamine adducts\n                      <jats:italic>in vitro<\/jats:italic>\n                      but without detail structural identification. The current work reports the identification of seven cyanide adducts that elucidate the bioactivation pathways and may provide hints for observed clinical adverse effects of the drug.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>METHODS<\/jats:title>\n                    <jats:p>\n                      Imatinib was incubated with human liver microsomal proteins in the presence of a NADPH\u2010regeneration system and the trapping agents reduced GSH, potassium cyanide and methoxylamine. Samples were analyzed by high\u2010performance liquid chromatography (HPLC) coupled with a LTQ\u2010Orbitrap data collection system. Chemical structures were determined and\/or postulated based on data\u2010dependent high\u2010resolution tandem mass spectrometric (MS\n                      <jats:sup>n<\/jats:sup>\n                      ) exact mass measurements in both positive and negative scan modes, as well as in combination with hydrogen\u2010deuterium exchange (HDX).\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>RESULTS<\/jats:title>\n                    <jats:p>\n                      GSH and methoxylamine conjugates were either not detected or were in insufficient quantities for characterization. However, seven cyanide conjugates were identified, indicating that the piperazine and\n                      <jats:italic>p<\/jats:italic>\n                      \u2010toluidine partial structures in imatinib can become bioactivated and subsequently trapped by the nucleophile cyanide ion. The reactive intermediates were postulated as imine and imine\u2010carbonyl conjugate (\u03b1,\u03b2\u2010unsaturated) structures on the piperazine ring, and imine\u2010methide on the\n                      <jats:italic>p<\/jats:italic>\n                      \u2010toluidine partial structure.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>CONCLUSIONS<\/jats:title>\n                    <jats:p>Chemical structures of seven cyanide adducts of imatinib have been identified or proposed based on high\u2010resolution MS\/MS data. Mechanisms for the formation of the conjugates were also proposed. The findings may help to understand the mechanism of hepatotoxicity of imatinib in humans. Copyright \u00a9 2013 John Wiley &amp; Sons, Ltd.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1002\/rcm.6758","type":"journal-article","created":{"date-parts":[[2013,11,21]],"date-time":"2013-11-21T00:52:30Z","timestamp":1384995150000},"page":"123-134","source":"Crossref","is-referenced-by-count":17,"title":["Structural identification of imatinib cyanide adducts by mass spectrometry and elucidation of bioactivation pathway"],"prefix":"10.1002","volume":"28","author":[{"given":"Austin C.","family":"Li","sequence":"first","affiliation":[{"name":"Drug Metabolism and Pharmacokinetics Teva Branded Pharmaceutical Products R&amp;D, Inc.  145 Brandywine Parkway West Chester PA 19380 USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Erya","family":"Yu","sequence":"additional","affiliation":[{"name":"Drug Metabolism and Pharmacokinetics Teva Branded Pharmaceutical Products R&amp;D, Inc.  145 Brandywine Parkway West Chester PA 19380 USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Steven C.","family":"Ring","sequence":"additional","affiliation":[{"name":"Drug Metabolism and Pharmacokinetics Teva Branded Pharmaceutical Products R&amp;D, Inc.  145 Brandywine Parkway West Chester PA 19380 USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"James P.","family":"Chovan","sequence":"additional","affiliation":[{"name":"Drug Metabolism and Pharmacokinetics Teva Branded Pharmaceutical Products R&amp;D, Inc.  145 Brandywine Parkway West Chester PA 19380 USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2013,11,21]]},"reference":[{"key":"e_1_2_6_2_1","doi-asserted-by":"publisher","DOI":"10.1080\/10245330500234195"},{"key":"e_1_2_6_3_1","doi-asserted-by":"publisher","DOI":"10.1001\/jama.286.1.35"},{"key":"e_1_2_6_4_1","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa020461"},{"key":"e_1_2_6_5_1","first-page":"935","article-title":"Approval summary for imatinib mesylate capsules in the treatment of chronic myelogenous leukemia","volume":"8","author":"Cohen M. 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