In vivo drug metabolism model for human cytochrome P450 enzyme using chimeric mice with humanized liver

J Pharm Sci. 2007 Feb;96(2):428-37. doi: 10.1002/jps.20783.

Abstract

We previously clarified that major human drug metabolizing enzymes were expressed in a chimeric urokinase-type plasminogen activator (uPA)+/+/severe combined immunodeficient (SCID) mouse line established recently, in which the liver could be replaced by more than 80% with human hepatocytes. In the present study, we investigated the in vivo drug metabolism of a CYP2D6 substrate, debrisoquin (DB), in chimeric mice with high (High) or low (Low) human albumin (hAlb) concentrations and in control uPA-/-/SCID mice. The hAlb in the mouse blood is one of the indices of humanized liver because the chimeric mice produce hAlb. After oral administration of DB at 2.0 mg/kg, the AUC0-8 value of a major CYP2D6 metabolite of DB, 4'-hydroxydebrisoquin (4-OH DB), in High was 3.6-fold higher than those of Low and uPA-/-/SCID mice. By pre-treatment with a typical CYP2D6 inhibitor, quinidine, the AUC0-8 value of 4-OH DB in High was decreased although such values in Low and uPA-/-/SCID mice did not change. The in vitro kinetic analyses and the Ki values of quinidine on the DB 4'-hydroxylase activity in liver microsomes also supported the humanization of the chimeric mice. In conclusion, the chimeric mice exhibited a humanized profile of drug metabolism and the inhibition of P450.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adrenergic Agents / blood
  • Adrenergic Agents / pharmacokinetics
  • Animals
  • Chimera*
  • Cytochrome P-450 CYP2D6 / metabolism*
  • Cytochrome P-450 CYP2D6 Inhibitors
  • Debrisoquin / analogs & derivatives
  • Debrisoquin / blood
  • Debrisoquin / pharmacokinetics*
  • Drug Interactions
  • Humans
  • Infant
  • Liver / drug effects
  • Liver / metabolism*
  • Male
  • Mice
  • Mice, SCID
  • Models, Animal*
  • Paroxetine / pharmacology
  • Quinidine / pharmacology
  • Urokinase-Type Plasminogen Activator / deficiency
  • Urokinase-Type Plasminogen Activator / genetics

Substances

  • Adrenergic Agents
  • Cytochrome P-450 CYP2D6 Inhibitors
  • Paroxetine
  • 4-hydroxydebrisoquin
  • Cytochrome P-450 CYP2D6
  • Urokinase-Type Plasminogen Activator
  • Quinidine
  • Debrisoquin