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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.

chemical research in toxicology

<i>In Vivo</i> Formation of Dihydroxylated and Glutathione Conjugate Metabolites Derived from Thalidomide and 5-Hydroxythalidomide in Humanized TK-NOG Mice

In Vivo Formation of Dihydroxylated and Glutathione Conjugate Metabolites Derived from Thalidomide and 5-Hydroxythalidomide in Humanized TK-NOG Mice