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

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

Volume: 10 Issue: 4

Author(s): Chiaki Tanoue, Kazumi Sugihara, Yoshitaka Tayama, Naoto Uramaru, Yoko Watanabe, Shigeru Ohta and Shigeyuki Kitamura*

Affiliation:

• Nihon Pharmaceutical University, Komuro 10281, Ina-machi, Kitaadachi-gun, Saitama 362-0806,Japan

Keywords: 5-oxo-zaleplon, aldehyde oxidase, interindividual variation, raloxifene, zaleplon.

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.

Cite this article as:

Tanoue Chiaki, Sugihara Kazumi, Tayama Yoshitaka, Uramaru Naoto, Watanabe Yoko, Ohta Shigeru and Kitamura Shigeyuki*, Variability of Zaleplon 5-Oxidase Activity in Mice and Humans, and Inhibition by Raloxifene, Drug Metabolism Letters 2016; 10 (4) . https://dx.doi.org/10.2174/1872312810666161227145358

DOI https://dx.doi.org/10.2174/1872312810666161227145358	Print ISSN 1872-3128
Publisher Name Bentham Science Publisher	Online ISSN 1874-0758