Prediction of human metabolism of the sedative-hypnotic zaleplon using chimeric mice transplanted with human hepatocytes

Xenobiotica. 2013 Nov;43(11):956-62. doi: 10.3109/00498254.2013.788232. Epub 2013 May 8.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Acetamides / blood
  • Acetamides / chemistry
  • Acetamides / metabolism*
  • Acetamides / pharmacokinetics
  • Administration, Oral
  • Adolescent
  • Animals
  • Cytosol / enzymology
  • Hepatocytes / metabolism*
  • Hepatocytes / transplantation*
  • Humans
  • Hypnotics and Sedatives / blood
  • Hypnotics and Sedatives / chemistry
  • Hypnotics and Sedatives / metabolism*
  • Hypnotics and Sedatives / pharmacokinetics
  • Liver / metabolism
  • Male
  • Metabolic Networks and Pathways
  • Mice
  • Mice, Transgenic
  • Microsomes, Liver / enzymology
  • Oxidoreductases / metabolism
  • Pyrimidines / blood
  • Pyrimidines / chemistry
  • Pyrimidines / metabolism*
  • Pyrimidines / pharmacokinetics
  • Rats
  • Time Factors

Substances

  • Acetamides
  • Hypnotics and Sedatives
  • Pyrimidines
  • Oxidoreductases
  • zaleplon