{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,9,13]],"date-time":"2025-09-13T15:46:20Z","timestamp":1757778380663,"version":"3.41.0"},"reference-count":33,"publisher":"Wiley","issue":"3","license":[{"start":{"date-parts":[[2018,3,13]],"date-time":"2018-03-13T00:00:00Z","timestamp":1520899200000},"content-version":"vor","delay-in-days":12,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"funder":[{"DOI":"10.13039\/501100004095","name":"Kyowa Hakko Kirin","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100004095","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Biopharm &amp; Drug Disp"],"published-print":{"date-parts":[[2018,3]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:p>We previously reported that KW\u20102449, (<jats:italic>E<\/jats:italic>)\u20101\u2010{4\u2010[2\u2010(1<jats:italic>H<\/jats:italic>\u2010Indazol\u20103\u2010yl)vinyl]benzoyl}piperazine, a novel multikinase inhibitor developed for the treatment of leukemia patients, was oxidized to an iminium ion intermediate by monoamine oxidase B (MAO\u2010B) and then converted to its oxo\u2010piperazine form (M1) by aldehyde oxidase (AO). However, it was found that the significant decrease in the pharmacologically active metabolite M1 following repeated administration of KW\u20102449 in primates might hamper the effectiveness of the drug. The mechanism underlying this phenomenon was investigated and it was found that the AO activity was inhibited in a time\u2010dependent manner<jats:italic>in vitro<\/jats:italic>under the co\u2010incubation of KW\u20102449 and MAO\u2010B, while neither KW\u20102449 nor M1 strongly inhibited MAO\u2010B or AO activity. These results clearly suggest that MAO\u2010B catalysed iminium ion metabolite inhibited AO, prompting us to investigate whether or not the iminium ion metabolite covalently binds to endogenous proteins, as has been reported with other reactive metabolites as a cause for idiosyncratic toxicity. The association of the radioactivity derived from<jats:sup>14<\/jats:sup>C\u2010KW\u20102449 with endogenous proteins both<jats:italic>in vivo<\/jats:italic>and<jats:italic>in vitro<\/jats:italic>was confirmed and it was verified that this covalent binding was inhibited by the addition of sodium cyanide, an iminium ion\u2010trapping reagent, and pargyline, a MAO\u2010B inhibitor. These findings strongly suggest that the iminium ion metabolite of KW\u20102449 is highly reactive in inhibiting AO irreversibly and binding to endogenous macromolecules covalently.<\/jats:p>","DOI":"10.1002\/bdd.2123","type":"journal-article","created":{"date-parts":[[2018,2,16]],"date-time":"2018-02-16T14:33:18Z","timestamp":1518791598000},"page":"164-174","source":"Crossref","is-referenced-by-count":8,"title":["An iminium ion metabolite hampers the production of the pharmacologically active metabolite of a multikinase inhibitor KW\u20102449 in primates: irreversible inhibition of aldehyde oxidase and covalent binding with endogenous proteins"],"prefix":"10.1002","volume":"39","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-9128-8406","authenticated-orcid":false,"given":"Jun","family":"Hosogi","sequence":"first","affiliation":[{"name":"Translational Research Unit Research and Development Division, Kyowa Hakko Kirin Co., Ltd 1188 Shimotogari, Nagaizumi\u2010cho, Sunto\u2010gun Shizuoka 411\u20108731 Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Rui","family":"Ohashi","sequence":"additional","affiliation":[{"name":"Translational Research Unit Research and Development Division, Kyowa Hakko Kirin Co., Ltd 1188 Shimotogari, Nagaizumi\u2010cho, Sunto\u2010gun Shizuoka 411\u20108731 Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Hiroshi","family":"Maeda","sequence":"additional","affiliation":[{"name":"Translational Research Unit Research and Development Division, Kyowa Hakko Kirin Co., Ltd 1188 Shimotogari, Nagaizumi\u2010cho, Sunto\u2010gun Shizuoka 411\u20108731 Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Kazuhiro","family":"Fujita","sequence":"additional","affiliation":[{"name":"Translational Research Unit Research and Development Division, Kyowa Hakko Kirin Co., Ltd 1188 Shimotogari, Nagaizumi\u2010cho, Sunto\u2010gun Shizuoka 411\u20108731 Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Junko","family":"Ushiki","sequence":"additional","affiliation":[{"name":"Translational Research Unit Research and Development Division, Kyowa Hakko Kirin Co., Ltd 1188 Shimotogari, Nagaizumi\u2010cho, Sunto\u2010gun Shizuoka 411\u20108731 Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Takashi","family":"Kuwabara","sequence":"additional","affiliation":[{"name":"Translational Research Unit Research and Development Division, Kyowa Hakko Kirin Co., Ltd 1188 Shimotogari, Nagaizumi\u2010cho, Sunto\u2010gun Shizuoka 411\u20108731 Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yorihiro","family":"Yamamoto","sequence":"additional","affiliation":[{"name":"School of Bioscience and Biotechnology Tokyo University of Technology 1404\u20101 Katakura\u2010cho, Hachioji Tokyo 192\u20100983 Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Toru","family":"Imamura","sequence":"additional","affiliation":[{"name":"School of Bioscience and Biotechnology Tokyo University of Technology 1404\u20101 Katakura\u2010cho, Hachioji Tokyo 192\u20100983 Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"311","published-online":{"date-parts":[[2018,3,13]]},"reference":[{"key":"e_1_2_7_2_1","doi-asserted-by":"publisher","DOI":"10.1046\/j.1472-8206.2001.00011.x"},{"key":"e_1_2_7_3_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.addr.2008.06.002"},{"key":"e_1_2_7_4_1","doi-asserted-by":"publisher","DOI":"10.1016\/0006-291X(79)91977-6"},{"issue":"2","key":"e_1_2_7_5_1","doi-asserted-by":"crossref","first-page":"251","DOI":"10.1016\/S0090-9556(25)06527-4","article-title":"Role of aldehyde oxidase in the in vitro conversion of famciclovir to penciclovir in human liver","volume":"23","author":"Clarke S. 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