Strain difference of oxidative metabolism of the sedative-hypnotic zaleplon by aldehyde oxidase and cytochrome P450 in vivo and in vitro in rats.
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.
Division of Medicinal Chemistry, Graduate School of Biomedical and Health Sciences, Hiroshima University, Japan.
Chiaki
C
Tanoue
Kazumi
K
Sugihara
Naoto
N
Uramaru
Yoko
Y
Watanabe
Yoshitaka
Y
Tayama
Shigeru
S
Ohta
Shigeyuki
S
Kitamura
D000081:Acetamides / Q000378:metabolism*; D042931:Aldehyde Oxidase / Q000378:metabolism*; D000818:Animals; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism*; D008297:Male; D011743:Pyrimidines / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D017208:Rats, Wistar; D013045:Species Specificity
D000081:Acetamides; D011743:Pyrimidines; D003577:Cytochrome P-450 Enzyme System; D042931:Aldehyde Oxidase; C085665:zaleplon