title: Variability of Zaleplon 5-Oxidase Activity in Mice and Humans, and Inhibition by Raloxifene.
abstract: 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.
  
  
  
  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.
  
  
  
  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.
  
  
  
  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.
authors.affiliation: Graduate School of Biomedical and Health Sciences, Hiroshima University, Kasumi 1-2-3, Minami-ku, Hiroshima 734- 8553. Japan.
authors.forename: Chiaki
authors.initials: C
authors.lastname: Tanoue
authors.affiliation: Faculty of Pharmaceutical Science, Hiroshima International University, Koshingai 5-1-1, Kure, Hiroshima 737-0112. Japan.
authors.forename: Kazumi
authors.initials: K
authors.lastname: Sugihara
authors.affiliation: Faculty of Pharmaceutical Science, Hiroshima International University, Koshingai 5-1-1, Kure, Hiroshima 737-0112. Japan.
authors.forename: Yoshitaka
authors.initials: Y
authors.lastname: Tayama
authors.affiliation: Nihon Pharmaceutical University, Komuro 10281, Ina-machi, Kitaadachi-gun, Saitama 362-0806. Japan.
authors.forename: Naoto
authors.initials: N
authors.lastname: Uramaru
authors.affiliation: Nihon Pharmaceutical University, Komuro 10281, Ina-machi, Kitaadachi-gun, Saitama 362-0806. Japan.
authors.forename: Yoko
authors.initials: Y
authors.lastname: Watanabe
authors.affiliation: Graduate School of Biomedical and Health Sciences, Hiroshima University, Kasumi 1-2-3, Minami-ku, Hiroshima 734- 8553. Japan.
authors.forename: Shigeru
authors.initials: S
authors.lastname: Ohta
authors.affiliation: Nihon Pharmaceutical University, Komuro 10281, Ina-machi, Kitaadachi-gun, Saitama 362-0806. Japan.
authors.forename: Shigeyuki
authors.initials: S
authors.lastname: Kitamura
mesh_terms: D000081:Acetamides / Q000378:metabolism*; D042931:Aldehyde Oxidase / Q000037:antagonists & inhibitors / Q000378:metabolism*; D000818:Animals; D000073537:Biological Variation, Population; D003600:Cytosol / Q000378:metabolism; D057075:Enzyme Assays; D005260:Female; D006801:Humans; D006993:Hypnotics and Sedatives / Q000378:metabolism*; D008099:Liver / Q000378:metabolism; D008297:Male; D051379:Mice; D008809:Mice, Inbred C3H; D008810:Mice, Inbred C57BL; D008811:Mice, Inbred DBA; D011743:Pyrimidines / Q000378:metabolism*; D020849:Raloxifene Hydrochloride / Q000494:pharmacology*; D012737:Sex Factors
chemical_list: D000081:Acetamides; D006993:Hypnotics and Sedatives; D011743:Pyrimidines; D020849:Raloxifene Hydrochloride; D042931:Aldehyde Oxidase; C085665:zaleplon
keywords: 5-oxo-zaleplon; aldehyde oxidase; interindividual variation; raloxifene; zaleplon