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 <i>in vivo</i> and <i>in vitro</i> metabolism of the sedative-hypnotic agent zaleplon (ZAL) to 5-hydroxylated ZAL (5-oxo-ZAL) and <i>N</i>-desethylated ZAL (desethyl-ZAL) was studied in four strains of rats. Incubation of ZAL with liver microsomes afforded desethyl-ZAL <i>via</i> 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 <i>in vivo</i> 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 <i>in vivo</i> in various strains of rats is primarily due to strain differences of hepatic aldehyde oxidase activity.<br>


  • Drug Metabolism and Pharmacokinetics

    Drug Metabolism and Pharmacokinetics 28(3), 269-273, 2013

    The Japanese Society for the Study of Xenobiotics


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