title: 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.
authors.affiliation: Showa Pharmaceutical University , Machida, Tokyo 194-8543, Japan.
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Yamazaki
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Suemizu
authors.forename: Makiko
authors.initials: M
authors.lastname: Shimizu
authors.forename: Sho
authors.initials: S
authors.lastname: Igaya
authors.forename: Norio
authors.initials: N
authors.lastname: Shibata
authors.forename: Masato
authors.initials: M
authors.lastname: Nakamura
authors.forename: Goutam
authors.initials: G
authors.lastname: Chowdhury
authors.forename: F Peter
authors.initials: FP
authors.lastname: Guengerich
mesh_terms: D000818:Animals; D002678:Chimera; D005978:Glutathione / Q000378:metabolism; D022781:Hepatocytes / Q000378:metabolism; D006801:Humans; D006900:Hydroxylation; D051379:Mice; D013723:Teratogens / Q000493:pharmacokinetics*; D013792:Thalidomide / Q000031:analogs & derivatives* / Q000097:blood / Q000378:metabolism / Q000493:pharmacokinetics*
chemical_list: C452282:5'-hydroxythalidomide; D013723:Teratogens; C544471:5-hydroxythalidomide; D013792:Thalidomide; D005978:Glutathione