Strain Difference of Oxidative Metabolism of the Sedative-hypnotic Zaleplon by Aldehyde Oxidase and Cytochrome P450 In Vivo and In Vitro in Rats
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- TANOUE Chiaki
- Division of Medicinal Chemistry, Graduate School of Biomedical and Health Sciences, Hiroshima University
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- SUGIHARA Kazumi
- Faculty of Pharmaceutical Sciences, Hiroshima International University
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- URAMARU Naoto
- Nihon Pharmaceutical University
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- WATANABE Yoko
- Nihon Pharmaceutical University
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- TAYAMA Yoshitaka
- Faculty of Pharmaceutical Sciences, Hiroshima International University
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- OHTA Shigeru
- Division of Medicinal Chemistry, Graduate School of Biomedical and Health Sciences, Hiroshima University
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- KITAMURA Shigeyuki
- Nihon Pharmaceutical University
書誌事項
- タイトル別名
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- Strain Difference of Oxidative Metabolism of the Sedative-hypnotic Zaleplon by Aldehyde Oxidase and Cytochrome P450 <i>In Vivo</i> and <i>In Vitro</i> in Rats
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The in vivo and in vitro metabolism of the sedative-hypnotic agent zaleplon (ZAL) to 5-hydroxylated ZAL (5-oxo-ZAL) and N-desethylated ZAL (desethyl-ZAL) was studied in four strains of rats. Incubation of ZAL with liver microsomes afforded desethyl-ZAL via cytochrome P450-catalyzed reaction, with little strain difference. In contrast, incubation of ZAL with liver cytosol afforded 5-oxo-ZAL with marked strain differences. ZAL hydroxylase activity was well correlated with aldehyde oxidase activity in these strains. The highest level of 5-oxo-ZAL and the highest activity of aldehyde oxidase were observed in cytosol from Sea:SD rats, followed by Jcl:SD rats, while Crj:SD and WKA/Sea rats showed low levels. When ZAL was administered to Sea:SD and WKA/Sea rats, both 5-oxo-ZAL and desethyl-ZAL were detected in blood as the major in vivo metabolites. However, the concentration of 5-oxo-ZAL was far higher in Sea:SD rats than in WKA/Sea rats, while that of desethyl-ZAL was far lower in Sea:SD rats. The levels of 5-oxo-ZAL in blood were closely correlated with the strain differences of cytosolic ZAL hydroxylase activity and benzaldehyde oxidase activity. Our results indicate that variability in the formation of 5-oxo-ZAL from ZAL in vivo in various strains of rats is primarily due to strain differences of hepatic aldehyde oxidase activity.<br>
収録刊行物
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- Ｄｒｕｇ Ｍｅｔａｂｏｌｉｓｍ ａｎｄ Ｐｈａｒｍａｃｏｋｉｎｅｔｉｃｓ
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Ｄｒｕｇ Ｍｅｔａｂｏｌｉｓｍ ａｎｄ Ｐｈａｒｍａｃｏｋｉｎｅｔｉｃｓ 28 (3), 269-273, 2013
日本薬物動態学会