title: Prediction of human metabolism of the sedative-hypnotic zaleplon using chimeric mice transplanted with human hepatocytes.
abstract: 1. Human chimeric mice (h-PXB mice) having humanized liver, constructed by transplantation of human hepatocytes, were evaluated as an experimental model for predicting human drug metabolism. Metabolism of zaleplon in h-PXB mice was compared with that in rat chimeric mice (r-PXB mice) constructed by transplantation of rat hepatocytes. 2. Zaleplon is metabolized to 5-oxo-zaleplon by aldehyde oxidase and to desethyl-zaleplon by cytochrome P450 (CYP3A4) in rat and human liver preparations. 3. Liver S9 fraction of h-PXB mice metabolized zaleplon to 5-oxo-zaleplon and desethyl-zaleplon in similar amounts. However, liver S9 fractions of r-PXB and control (urokinase-type plasminogen activator-transgenic severe combined immunodeficient) mice predominantly metabolized zaleplon to desethyl-zaleplon. 5-Oxo-zaleplon was detected as a minor metabolite. 4. Oxidase activity of h-PXB mouse liver cytosol toward zaleplon was about 10-fold higher than that of r-PXB or control mice. In contrast, activities for desethyl-zaleplon formation were similar in liver microsomes from these mice, as well as rat and human liver microsomes. 5. In vivo, the level of 5-oxo-zaleplon in plasma of h-PXB mice was about 7-fold higher than that in r-PXB or control mice, in agreement with the in vitro data. Thus, aldehyde oxidase in h-PXB mice functions as human aldehyde oxidase, both in vivo and in vitro. 6. In contrast, the plasma level of desethyl-zaleplon in r-PXB and control mice was higher than that in h-PXB mice. 7. These results suggest h-PXB mice with humanized liver could be a useful experimental model to predict aldehyde oxidase- and CYP3A4-mediated drug metabolism in humans.
authors: Graduate School of Biomedical and Health Sciences, Hiroshima University , Kasumi 1-2-3, Minami-ku, Hiroshima, 734-8553 , Japan .
authors: Chiaki
authors: C
authors: Tanoue
authors: Kazumi
authors: K
authors: Sugihara
authors: Naoto
authors: N
authors: Uramaru
authors: Yoshitaka
authors: Y
authors: Tayama
authors: Yoko
authors: Y
authors: Watanabe
authors: Toru
authors: T
authors: Horie
authors: Shigeru
authors: S
authors: Ohta
authors: Shigeyuki
authors: S
authors: Kitamura
mesh_terms: D000081:Acetamides / Q000097:blood / Q000737:chemistry / Q000378:metabolism* / Q000493:pharmacokinetics; D000284:Administration, Oral; D000293:Adolescent; D000818:Animals; D003600:Cytosol / Q000201:enzymology; D022781:Hepatocytes / Q000378:metabolism* / Q000637:transplantation*; D006801:Humans; D006993:Hypnotics and Sedatives / Q000097:blood / Q000737:chemistry / Q000378:metabolism* / Q000493:pharmacokinetics; D008099:Liver / Q000378:metabolism; D008297:Male; D053858:Metabolic Networks and Pathways; D051379:Mice; D008822:Mice, Transgenic; D008862:Microsomes, Liver / Q000201:enzymology; D010088:Oxidoreductases / Q000378:metabolism; D011743:Pyrimidines / Q000097:blood / Q000737:chemistry / Q000378:metabolism* / Q000493:pharmacokinetics; D051381:Rats; D013997:Time Factors
chemical_list: D000081:Acetamides; D006993:Hypnotics and Sedatives; D011743:Pyrimidines; D010088:Oxidoreductases; C085665:zaleplon