title: In vivo drug interactions of the teratogen thalidomide with midazolam: heterotropic cooperativity of human cytochrome P450 in humanized TK-NOG mice.
abstract: In vivo drug interactions of the teratogen thalidomide with the model cytochrome P450 (P450) 3A substrate midazolam were investigated in mice with humanized livers. The clearance of midazolam (administered intravenously, 10 mg kg(-1)) in chimeric mice was enhanced by orally co-administered thalidomide (100 mg kg(-1)). A larger area under the curve of the major metabolite 1'-hydroxymidazolam (1.7-fold) was obtained with thalidomide because of the heterotropic cooperativity of human P450 3A enzymes. A larger area under the curve of the minor metabolite 4-hydroxymidazolam (3.5-fold) was seen with daily pretreatment with thalidomide for 3 days, presumably because of human P450 3A induction. These results demonstrate that livers of humanized mice mediate drug interactions of thalidomide and suggest interactions of therapeutic agents during therapies with thalidomide.
authors: Showa Pharmaceutical University , Machida, Tokyo, Japan. hyamazak@ac.shoyaku.ac.jp
authors: Hiroshi
authors: H
authors: Yamazaki
authors: Hiroshi
authors: H
authors: Suemizu
authors: Norie
authors: N
authors: Murayama
authors: Masahiro
authors: M
authors: Utoh
authors: Norio
authors: N
authors: Shibata
authors: Masato
authors: M
authors: Nakamura
authors: F Peter
authors: FP
authors: Guengerich
mesh_terms: D000759:Adjuvants, Anesthesia / Q000008:administration & dosage / Q000097:blood / Q000378:metabolism / Q000494:pharmacology*; D000818:Animals; D002678:Chimera / Q000378:metabolism; D051544:Cytochrome P-450 CYP3A / Q000378:metabolism*; D004347:Drug Interactions; D005260:Female; D006801:Humans; D007166:Immunosuppressive Agents / Q000008:administration & dosage / Q000378:metabolism / Q000494:pharmacology*; D008099:Liver / Q000378:metabolism*; D008297:Male; D051379:Mice; D008874:Midazolam / Q000008:administration & dosage / Q000097:blood / Q000378:metabolism / Q000494:pharmacology*; D013723:Teratogens / Q000378:metabolism / Q000494:pharmacology*; D013792:Thalidomide / Q000008:administration & dosage / Q000378:metabolism / Q000494:pharmacology*
chemical_list: D000759:Adjuvants, Anesthesia; D007166:Immunosuppressive Agents; D013723:Teratogens; D013792:Thalidomide; D051544:Cytochrome P-450 CYP3A; D008874:Midazolam