Kawashima K, Hosoi K, Naruke T, Shiba T, Kitamura M, Watabe T
Department of Pharmacokinetics, Medical Research Laboratories, Lederle (Japan), Ltd., Saitama, Japan.
Drug Metab Dispos. 1999 Mar;27(3):422-8.
A marked difference in hepatic activity of aldehyde oxidase between rats and monkeys was found to be responsible for the previously reported marked species difference in the metabolism of Zaleplon in vivo. In the postmitochondrial fractions, S-9s, from liver homogenates of these animals, Zaleplon was transformed in the presence of NADPH into the side chain oxidation product, N-desethyl-Zaleplon, and the aromatic ring oxidation product, 5-oxo-Zaleplon. In the rat S-9, N-desethyl-Zaleplon and 5-oxo-Zaleplon were a major and a very minor metabolites, respectively. However, in the monkey S-9, Zaleplon was transformed into 5-oxo-Zaleplon at a much higher rate than that for N-desethyl-Zaleplon formation. N-Desethyl-Zaleplon was formed in the monkey S-9 at a rate almost equal to that in the rat S-9. N-Desethyl-5-oxo-Zaleplon was formed at a minor rate only in the monkey S-9 through N-desethyl-Zaleplon as an obligatory intermediate. The hepatic activity for the formation of 5-oxo-Zaleplon in the monkey and rat was localized in cytosol and did not require NADPH. Sensitivity to various inhibitors and requirement of water as oxygen source, using H218O, strongly suggested that the hepatic cytosolic formation of 5-oxo-Zaleplon was mediated by aldehyde oxidase. N-Desethyl-Zaleplon was formed in the presence of NADPH by microsomes from the liver of rats and monkeys, and its formation was strongly suggested using various cytochrome P-450 inhibitors to be mediated by a number of cytochrome P-450 isoforms, such as 3A, 2C, and 2D subfamilies.
研究发现，大鼠和猴子肝脏中醛氧化酶的活性存在显著差异，这是此前报道的扎来普隆体内代谢存在显著种属差异的原因。在这些动物肝脏匀浆的线粒体后组分（S-9）中，扎来普隆在NADPH存在的情况下转化为侧链氧化产物N-去乙基扎来普隆和芳香环氧化产物5-氧代扎来普隆。在大鼠S-9中，N-去乙基扎来普隆和5-氧代扎来普隆分别是主要和非常次要的代谢产物。然而，在猴子S-9中，扎来普隆转化为5-氧代扎来普隆的速率远高于形成N-去乙基扎来普隆的速率。猴子S-9中形成N-去乙基扎来普隆的速率几乎与大鼠S-9中的相同。N-去乙基-5-氧代扎来普隆仅在猴子S-9中以较低的速率通过N-去乙基扎来普隆作为必需中间体形成。猴子和大鼠肝脏中形成5-氧代扎来普隆的活性定位于胞质溶胶中，且不需要NADPH。使用H₂¹⁸O对各种抑制剂的敏感性以及对水作为氧源的需求强烈表明，肝脏胞质溶胶中5-氧代扎来普隆的形成是由醛氧化酶介导的。N-去乙基扎来普隆在大鼠和猴子肝脏微粒体存在NADPH的情况下形成，使用各种细胞色素P-450抑制剂强烈表明其形成是由多种细胞色素P-450同工型介导的，如3A、2C和2D亚家族。
