TY - JOUR T1 - Aldehyde Oxidase-Dependent Marked Species Difference in Hepatic Metabolism of the Sedative-Hypnotic, Zaleplon, Between Monkeys and Rats JF - Drug Metabolism and Disposition JO - Drug Metab Dispos SP - 422 LP - 428 VL - 27 IS - 3 AU - Kosuke Kawashima AU - Kenichi Hosoi AU - Takeshi Naruke AU - Toshiharu Shiba AU - Masataka Kitamura AU - Tadashi Watabe Y1 - 1999/03/01 UR - http://dmd.aspetjournals.org/content/27/3/422.abstract N2 - 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 monkeyS-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 monkeyS-9 at a rate almost equal to that in the ratS-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. The American Society for Pharmacology and Experimental Therapeutics ER -