2014年4月
In vivo effects of the pure aryl hydrocarbon receptor antagonist GNF-351 after oral administration are limited to the gastrointestinal tract.
British journal of pharmacology
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- 巻
- 171
- 号
- 7
- 開始ページ
- 1735
- 終了ページ
- 46
- 記述言語
- 英語
- 掲載種別
- 研究論文(学術雑誌)
- DOI
- 10.1111/bph.12576
BACKGROUND AND PURPOSE: GNF-351 is a potent aryl hydrocarbon receptor (AHR) antagonist that inhibits dioxin response element-dependent and independent activities. Here, the absorption, metabolism and in vivo AHR antagonist activity of GNF-351 were investigated. EXPERIMENTAL APPROACH: LC-MS metabolomics was used to analyse GNF-351 metabolism in vitro and in vivo. Recombinant drug-metabolizing enzymes were employed to determine the enzymes involved in GNF-351 metabolism. Analysis of target AHR genes was performed to investigate the inhibitory effects of GNF-351 towards AHR activation. KEY RESULTS: Several phase I metabolites were generated after GNF-351 was incubated with microsomes from human or mouse liver and intestine, including two oxidized GNF-351 and one tri-demethylated GNF-351. Poor absorption from the intestine resulted in no detectable levels of GNF-351 in mouse serum (0-6 h) and urine (24 h) and almost all GNF-351 was found in the faeces after 24 h. Analysis of faeces further revealed all the in vitro phase I metabolites. Novel metabolites were detected, including one di-oxidized GNF-351, two oxidized and tri-demethylated GNF-351, one dehydrogenated product of oxidized GNF-351, and one sulfation product of di-oxidized GNF-351. Cytochromes P450 were demonstrated to be the major enzymes involved in metabolism of GNF-351. After oral administration to mice, GNF-351 readily inhibited β-naphthoflavone-induced AHR activation in ileum and colon, but not that in the liver. CONCLUSION AND IMPLICATIONS: While poor absorption and extensive metabolism after oral administration limited the in vivo effects of the pure AHR antagonist GNF-351 in liver, it could be used to inhibit AHR activation in intestine and colon.
- リンク情報
- ID情報
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- DOI : 10.1111/bph.12576
- PubMed ID : 24417285
- PubMed Central 記事ID : PMC3966752