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埼玉医科大学雑誌 第30巻 第4号 (2003年10月) 187-194頁 ◇論文(図表を含む全文)は，PDFファイルとなっています． PDF (1.8 MB) 原 著 Benzbromarone (Urinorm®)の代謝・毒性および薬理作用に関する研究 国嶋 千代子1)，井上 郁夫2)，及川 寿浩1)，片山 茂裕2) 1）鳥居薬品株式会社医薬情報部 2）埼玉医科大学第四内科学教室 〔平成15年8月8日受付〕 The Metabolism, Toxicity and Pharmacological Studies of Benzbromarone (Urinorm®) Chiyoko Kunishimaa, Ikuo Inoueb, Toshihiro Oikawaa, Shigehiro Katayamab (aPharmacovigilance Department of Torii Pharmaceutical Co., Ltd, 3-4-1, Nihonbashihoncho, Chuo-ku, Tokyo 103-8439, Japan and bFourth Department of Internal Medicine, Medical School, Moroyama, Iruma-gun, Saitama 350-0495, Japan) Sporadic reports of mild hepatic dysfunction as an adverse reaction of Benzbromarone have appeared in recent years, and in some cases, fulminant hepatitis has developed. We first investigated metabolites of Benzbromarone, using LC/MS, and identified the metabolites of Benzbromarone in vitro. Results showed that human liver S9 metabolites of Benzbromarone consist of two hydroxy bodies, two monohydroxy bodies and five 1’-ketone bodies; previous reports (except that debromination products were not detected) suggest that Benzarone (possibly related to hepatotoxicity) is not formed in humans. We also identified CYP molecular species related to the metabolism of Benzbromarone, by use of a human P450-expressing microsome system. We found that Benzbromarone is metabolized by CYP2C9*1 and 2C9*2, and the main metabolite is 6-hydroxylbenzbromarone. A study of the inhibitory action of Benzbromarone on human P450 molecular species showed that Benzbromarone has especially potent inhibitory action on CYP2C8/9. Therefore, it was clear that Benzbromarone is metabolized by CYP2C9 and inhibits CYP2C8 and CYP2C9. Deaths caused by fulminant hepatitis in patients given the antidiabetic troglitazone (Noscal), a peroxisome proliferator-activated receptor (PPAR)-γ agonist, have recently been reported. It has also been reported that the mechanism of onset is by the induction of hepatocellular apoptosis by excessive increase of PPAR-γ activity. Because Benzbromarone has long been considered to be a peroxisome proliferating agent, we studied the action of Benzbromarone on PPAR-α and PPAR-γ. The results indicated that Benzbromarone is a ligand of PPAR-α. Our results suggest that the hepatic dysfunction associated with Benzbromarone is not caused by apoptosis. Keywords: Benzbromarone, PPAR, CYP J Saitama Med School 2003;30:187-194 (Received August 8, 2003)
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