{"@context":{"@vocab":"https://cir.nii.ac.jp/schema/1.0/","rdfs":"http://www.w3.org/2000/01/rdf-schema#","dc":"http://purl.org/dc/elements/1.1/","dcterms":"http://purl.org/dc/terms/","foaf":"http://xmlns.com/foaf/0.1/","prism":"http://prismstandard.org/namespaces/basic/2.0/","cinii":"http://ci.nii.ac.jp/ns/1.0/","datacite":"https://schema.datacite.org/meta/kernel-4/","ndl":"http://ndl.go.jp/dcndl/terms/","jpcoar":"https://github.com/JPCOAR/schema/blob/master/2.0/"},"@id":"https://cir.nii.ac.jp/crid/1390001205546156032.json","@type":"Article","productIdentifier":[{"identifier":{"@type":"DOI","@value":"10.14869/toxpt.40.1.0.1003038.0"}},{"identifier":{"@type":"NAID","@value":"130004676518"}}],"dc:title":[{"@language":"en","@value":"Involvement of metabolic activation of carbamazepine in liver injury in rat"},{"@language":"ja","@value":"ラットにおける代謝を考慮したカルバマゼピン誘導性肝障害のメカニズム解析"}],"dc:language":"ja","description":[{"type":"abstract","notation":[{"@language":"ja","@value":"【目的】薬物誘導性肝障害は医薬品開発および薬物治療において重大な問題である。肝障害発症には代謝酵素により生成される反応性代謝物の関与が考えられているが，薬物誘導性肝障害の動物モデルを用いて肝障害と代謝物の関与を明らかにした報告は極めて少ない。本検討ではラットを用いて，副作用として肝障害が報告されているcarbamazepine (CBZ) による肝障害モデルを作製し，経時的に代謝物の血漿中濃度を測定することにより発症メカニズムを明らかにすることを目的とした。<br>【実験方法】9週齢の雄性F344ラットにCBZ (400 mg/kg in corn oil, <i>p.o.</i>)を4日間投与し，5日目にCBZ (600 mg/kg) とglutathione (GSH) 合成阻害剤であるL-buthionine sulfoximine (BSO: 700 mg/kg in saline, <i>i.p.</i>) を併用投与した。その後，経時的に血漿および肝臓を採取し，血漿中のALT値とAST値の測定および肝臓の組織学的評価を行った。また，HPLCによりCBZとその代謝物の血漿中濃度を測定した。CYP3A阻害剤であるketoconazole (KTZ) およびtroleandomycin (TAO) または誘導剤であるdexamethazone (DEX) の投与により，肝障害に対するCYP3Aの影響を検討した。<br>【結果および考察】BSO併用投与によりCBZ最終投与24時間後に約半数の個体において，ALT値およびAST値の顕著な上昇と肝組織において広範なネクロ―シスが認められ，GSH枯渇下での反応性代謝物の生成が肝障害発症に関与する可能性が考えられた。2-OH CBZや3-OH CBZの血漿中濃度測定を行ったが，肝障害が発症した個体と発症していない個体間で大きな差は認められなかった。KTZまたはTAOの併用投与により，全ての個体においてALT値の上昇は認められなかった。一方，DEXによるCYP3Aの誘導後，BSOとCBZ 400 mg/kg単回投与によって肝障害が惹起された。以上の結果から，原因代謝物はまだ同定できていないものの，CYP3Aによる代謝が肝障害の惹起に関与することが示唆された。"}],"abstractLicenseFlag":"disallow"}],"creator":[{"@id":"https://cir.nii.ac.jp/crid/1410290696166481152","@type":"Researcher","personIdentifier":[{"@type":"NRID","@value":"9000258714342"}],"foaf:name":[{"@language":"en","@value":"YANO azusa"},{"@language":"ja","@value":"矢野 梓"}],"jpcoar:affiliationName":[{"@language":"en","@value":"Drug Metabolism and Toxicology, Faculty of Pharmaceutical Sciences, Kanazawa University"},{"@language":"ja","@value":"金沢大学　医薬保健研究域　薬学系　薬物代謝化学研究室"}]},{"@id":"https://cir.nii.ac.jp/crid/1410290696166481157","@type":"Researcher","personIdentifier":[{"@type":"NRID","@value":"9000258714343"}],"foaf:name":[{"@language":"en","@value":"TSUNEYAMA koichi"},{"@language":"ja","@value":"常山 幸一"}],"jpcoar:affiliationName":[{"@language":"en","@value":"Department of Diagnostic Pathology, Graduate School of Medicine and Pharmaceutical Science for Research, University of Toyama"},{"@language":"ja","@value":"富山大学　医学薬学研究部　病理診断学講座"}]},{"@id":"https://cir.nii.ac.jp/crid/1420564276180840192","@type":"Researcher","personIdentifier":[{"@type":"KAKEN_RESEARCHERS","@value":"00532300"},{"@type":"NRID","@value":"1000000532300"},{"@type":"NRID","@value":"9000283795223"},{"@type":"NRID","@value":"9000391992269"},{"@type":"NRID","@value":"9000257892742"},{"@type":"NRID","@value":"9000356480781"},{"@type":"NRID","@value":"9000347193455"},{"@type":"NRID","@value":"9000391992487"},{"@type":"NRID","@value":"9000257892057"},{"@type":"NRID","@value":"9000258575825"},{"@type":"NRID","@value":"9000415156890"},{"@type":"NRID","@value":"9000288798536"},{"@type":"NRID","@value":"9000283795238"},{"@type":"NRID","@value":"9000410151225"},{"@type":"NRID","@value":"9000258575919"},{"@type":"NRID","@value":"9000415176847"},{"@type":"NRID","@value":"9000242351277"},{"@type":"NRID","@value":"9000283795402"},{"@type":"NRID","@value":"9000283798394"},{"@type":"NRID","@value":"9000391992264"},{"@type":"NRID","@value":"9000258574165"},{"@type":"NRID","@value":"9000017478355"},{"@type":"NRID","@value":"9000288798529"},{"@type":"NRID","@value":"9000415171055"},{"@type":"NRID","@value":"9000409576122"},{"@type":"NRID","@value":"9000409576127"},{"@type":"NRID","@value":"9000391994984"},{"@type":"NRID","@value":"9000258714332"},{"@type":"NRID","@value":"9000258575925"},{"@type":"NRID","@value":"9000415220415"},{"@type":"NRID","@value":"9000024128657"},{"@type":"NRID","@value":"9000347140835"},{"@type":"NRID","@value":"9000347140792"},{"@type":"NRID","@value":"9000347194160"},{"@type":"NRID","@value":"9000391998275"},{"@type":"NRID","@value":"9000258575832"},{"@type":"NRID","@value":"9000258573682"},{"@type":"NRID","@value":"9000415235238"},{"@type":"NRID","@value":"9000023241741"},{"@type":"NRID","@value":"9000022888493"},{"@type":"NRID","@value":"9000024705486"},{"@type":"NRID","@value":"9000309570870"},{"@type":"NRID","@value":"9000391992280"},{"@type":"NRID","@value":"9000391995205"},{"@type":"NRID","@value":"9000392002028"},{"@type":"NRID","@value":"9000258714344"},{"@type":"NRID","@value":"9000258575200"},{"@type":"NRID","@value":"9000258575602"},{"@type":"NRID","@value":"9000258577373"},{"@type":"NRID","@value":"9000386308402"},{"@type":"NRID","@value":"9000283730212"},{"@type":"NRID","@value":"9000391992681"},{"@type":"NRID","@value":"9000283571242"},{"@type":"NRID","@value":"9000258575915"},{"@type":"NRID","@value":"9000258575948"},{"@type":"NRID","@value":"9000258574268"},{"@type":"NRID","@value":"9000258576862"},{"@type":"NRID","@value":"9000283729414"},{"@type":"NRID","@value":"9000391994658"},{"@type":"NRID","@value":"9000257820845"},{"@type":"NRID","@value":"9000258577195"},{"@type":"NRID","@value":"9000415181187"},{"@type":"NRID","@value":"9000283730266"},{"@type":"NRID","@value":"9000283730712"},{"@type":"NRID","@value":"9000397799609"},{"@type":"NRID","@value":"9000391991913"},{"@type":"NRID","@value":"9000258712978"},{"@type":"NRID","@value":"9000258575277"},{"@type":"NRID","@value":"9000258574264"},{"@type":"NRID","@value":"9000415177992"},{"@type":"NRID","@value":"9000391994990"},{"@type":"NRID","@value":"9000391995003"},{"@type":"NRID","@value":"9000392002033"},{"@type":"NRID","@value":"9000258714366"},{"@type":"NRID","@value":"9000258714355"},{"@type":"NRID","@value":"9000258714350"},{"@type":"NRID","@value":"9000397802664"},{"@type":"NRID","@value":"9000410151226"},{"@type":"NRID","@value":"9000391993973"},{"@type":"NRID","@value":"9000240120716"},{"@type":"NRID","@value":"9000347140975"},{"@type":"NRID","@value":"9000391993389"},{"@type":"NRID","@value":"9000258574217"},{"@type":"NRID","@value":"9000258575608"},{"@type":"NRID","@value":"9000283798765"},{"@type":"NRID","@value":"9000258576182"},{"@type":"NRID","@value":"9000258576215"},{"@type":"NRID","@value":"9000415202773"},{"@type":"NRID","@value":"9000415136364"},{"@type":"NRID","@value":"9000288798524"},{"@type":"NRID","@value":"9000347046579"},{"@type":"NRID","@value":"9000347140147"},{"@type":"NRID","@value":"9000391993393"},{"@type":"NRID","@value":"9000258713228"},{"@type":"RESEARCHMAP","@value":"https://researchmap.jp/tatsukifukami"}],"foaf:name":[{"@language":"en","@value":"FUKAMI Tatsuki"},{"@language":"ja","@value":"深見 達基"}],"jpcoar:affiliationName":[{"@language":"en","@value":"Drug Metabolism and Toxicology, Faculty of Pharmaceutical Sciences, Kanazawa University"},{"@language":"ja","@value":"金沢大学　医薬保健研究域　薬学系　薬物代謝化学研究室"}]},{"@id":"https://cir.nii.ac.jp/crid/1410290696166481154","@type":"Researcher","personIdentifier":[{"@type":"NRID","@value":"9000258714345"}],"foaf:name":[{"@language":"en","@value":"NAKAJIMA Miki"},{"@language":"ja","@value":"中島 美紀"}],"jpcoar:affiliationName":[{"@language":"en","@value":"Drug Metabolism and Toxicology, Faculty of Pharmaceutical Sciences, Kanazawa University"},{"@language":"ja","@value":"金沢大学　医薬保健研究域　薬学系　薬物代謝化学研究室"}]},{"@id":"https://cir.nii.ac.jp/crid/1410290696166481155","@type":"Researcher","personIdentifier":[{"@type":"NRID","@value":"9000258714346"}],"foaf:name":[{"@language":"en","@value":"YOKOI Tsuyoshi"},{"@language":"ja","@value":"横井 毅"}],"jpcoar:affiliationName":[{"@language":"en","@value":"Drug Metabolism and Toxicology, Faculty of Pharmaceutical Sciences, Kanazawa University"},{"@language":"ja","@value":"金沢大学　医薬保健研究域　薬学系　薬物代謝化学研究室"}]},{"@id":"https://cir.nii.ac.jp/crid/1410290696166481153","@type":"Researcher","personIdentifier":[{"@type":"NRID","@value":"9000258714341"}],"foaf:name":[{"@language":"en","@value":"IIDA Azumi"},{"@language":"ja","@value":"飯田 あずみ"}],"jpcoar:affiliationName":[{"@language":"en","@value":"Drug Metabolism and Toxicology, Faculty of Pharmaceutical Sciences, Kanazawa University"},{"@language":"ja","@value":"金沢大学　医薬保健研究域　薬学系　薬物代謝化学研究室"}]}],"publication":{"prism:publicationName":[{"@language":"en","@value":"Annual Meeting of the Japanese Society of Toxicology"},{"@language":"ja","@value":"日本毒性学会学術年会"}],"dc:publisher":[{"@language":"en","@value":"The Japanese Society of Toxicology"},{"@language":"ja","@value":"日本毒性学会"}],"prism:publicationDate":"2013","prism:volume":"40.1","prism:number":"0","prism:startingPage":"1003038"},"availableAt":"2013","foaf:topic":[{"@id":"https://cir.nii.ac.jp/all?q=carbamazepine","dc:title":"carbamazepine"},{"@id":"https://cir.nii.ac.jp/all?q=liver%20injury","dc:title":"liver injury"},{"@id":"https://cir.nii.ac.jp/all?q=metabolic%20activation","dc:title":"metabolic activation"},{"@id":"https://cir.nii.ac.jp/all?q=%E3%82%AB%E3%83%AB%E3%83%90%E3%83%9E%E3%82%BC%E3%83%94%E3%83%B3","dc:title":"カルバマゼピン"},{"@id":"https://cir.nii.ac.jp/all?q=%E8%82%9D%E9%9A%9C%E5%AE%B3","dc:title":"肝障害"},{"@id":"https://cir.nii.ac.jp/all?q=%E4%BB%A3%E8%AC%9D%E7%9A%84%E6%B4%BB%E6%80%A7%E5%8C%96","dc:title":"代謝的活性化"}],"dataSourceIdentifier":[{"@type":"JALC","@value":"oai:japanlinkcenter.org:1003281340"},{"@type":"CIA","@value":"130004676518"}]}