Variability of Zaleplon 5-Oxidase Activity in Mice and Humans, and Inhibition by Raloxifene.

Drug metabolism letters Pub Date : 2017-01-01 DOI:10.2174/1872312810666161227145358

Chiaki Tanoue, K. Sugihara, Y. Tayama, Naoto Uramaru, Yoko Watanabe, S. Ohta, S. Kitamura

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引用次数: 5

Abstract

BACKGROUND Zaleplon (ZAL) is a sedative-hypnotic agent, which is mainly metabolized to inactive 5-oxidized zaleplon (5-oxo-ZAL) and N-des-ethylated ZAL (des-ethyl-ZAL) in mice and humans. The former reaction is considered to be catalyzed by aldehyde oxidase present in liver cytosol. METHODS Here, we examined sex and strain differences of ZAL metabolism to 5-oxo-ZAL among four strains of mice, as well as the inter-individual variation in humans, in order to evaluate the variability of 5-oxo-ZAL-forming activity and its relationship with aldehyde oxidase activity. In mice, the activity in C57BL/6J strain was the highest, followed by C3H/He and BALB/c. The activity in DBA/2J was the lowest, being 2.3-fold lower than that of C57BL/6J mice. The activity of male mice was higher than that of female mice. Large inter-individual variations were observed among humans, with a range of 10- fold. Raloxifene, an inhibitor of aldehyde oxidase, markedly decreased the formation of 5-oxo-ZAL by liver cytosol of mice and humans. Further, the plasma level of 5-oxo-ZAL in mice was decreased when raloxifene was co-administered with ZAL. RESULTS Our results indicate that the formation of 5-oxo-ZAL from ZAL is mainly catalyzed by aldehyde oxidase in mice and humans, and the variability of 5-oxo-ZAL formation is due primarily to differences of aldehyde oxidase activity. CONCLUSION High inter-individual variability of ZAL 5-oxidase activity and potential for interaction of ZAL with other medicines that are inhibitors of aldehyde oxidase should be taken into consideration in clinical usage of ZAL.

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小鼠和人扎来普龙5-氧化酶活性的变异性及雷洛昔芬的抑制作用。

扎来普隆(ZAL)是一种镇静催眠药物，在小鼠和人体内主要代谢为无活性的5-氧化扎来普隆(5-oxo-ZAL)和n -去乙基化扎来普隆(去乙基-ZAL)。前一反应被认为是由肝细胞质中存在的醛氧化酶催化的。方法通过对4个小鼠品系中ZAL对5-oxo-ZAL代谢的性别、品系差异以及人类个体间差异进行分析，探讨5-oxo-ZAL形成活性的变异性及其与醛氧化酶活性的关系。在小鼠中，C57BL/6J株活性最高，其次是C3H/He和BALB/c。其中DBA/2J组活性最低，比C57BL/6J组低2.3倍。雄性小鼠的活性高于雌性小鼠。在人类中观察到很大的个体间差异，范围为10倍。雷洛昔芬是一种醛氧化酶抑制剂，能显著减少小鼠和人肝细胞质中5-oxo-ZAL的形成。此外，当雷洛昔芬与ZAL合用时，小鼠血浆中5-oxo-ZAL水平降低。结果小鼠和人体内ZAL主要由醛氧化酶催化生成5-oxo-ZAL, 5-oxo-ZAL生成的差异性主要是由于醛氧化酶活性的差异。结论临床应用ZAL时应考虑ZAL 5氧化酶活性的个体差异性及与其他醛氧化酶抑制剂药物的相互作用。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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Drug metabolism letters Pharmacology, Toxicology and Pharmaceutics-Pharmaceutical Science

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期刊介绍： Drug Metabolism Letters publishes letters and research articles on major advances in all areas of drug metabolism and disposition. The emphasis is on publishing quality papers very rapidly by taking full advantage of the Internet technology both for the submission and review of manuscripts. The journal covers the following areas: In vitro systems including CYP-450; enzyme induction and inhibition; drug-drug interactions and enzyme kinetics; pharmacokinetics, toxicokinetics, species scaling and extrapolations; P-glycoprotein and transport carriers; target organ toxicity and interindividual variability; drug metabolism and disposition studies; extrahepatic metabolism; phase I and phase II metabolism; recent developments for the identification of drug metabolites.