In vivo formation of dihydroxylated and glutathione conjugate metabolites derived from thalidomide and 5-Hydroxythalidomide in humanized TK-NOG mice.

ABSTRACT: The formation of dihydroxythalidomide and glutathione (GSH) conjugate(s) of 5-hydroxythalidomide was investigated in chimeric mice modified with "humanized" liver: novel humanized TK-NOG mice were prepared by the introduction of thymidine kinase, followed by induction with ganciclovir, and human liver cells were transplanted. Following oral administration of racemic thalidomide (100 mg/kg), plasma concentrations of 5-hydroxy- and dihydroxythalidomide were higher in humanized mice than in controls. After administration of 5-hydroxythalidomide (10 mg/kg), higher concentrations of dihydroxythalidomide were detected. These results indicate that livers of humanized mice mediate thalidomide oxidation, leading to catechol and/or the GSH conjugate in vivo and suggest that thalidomide activation occurs.

SUBMITTER: Yamazaki H 

PROVIDER: S-EPMC3976424 | biostudies-literature | 2012 Feb

REPOSITORIES: biostudies-literature