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Chem Res Toxicol. 2013 Mar 18;26(3):486-9. doi: 10.1021/tx400008g. Epub 2013 Mar 1.

In vivo drug interactions of the teratogen thalidomide with midazolam: heterotropic cooperativity of human cytochrome P450 in humanized TK-NOG mice.

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1
Showa Pharmaceutical University , Machida, Tokyo, Japan. hyamazak@ac.shoyaku.ac.jp

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.

PMID:
23419139
PMCID:
PMC4049203
DOI:
10.1021/tx400008g
[Indexed for MEDLINE]
Free PMC Article
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