2012年3月
Substrate/Product-Targeted NMR Monitoring of Pyrimidine Catabolism and Its Inhibition by a Clinical Drug
ACS CHEMICAL BIOLOGY
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- 巻
- 7
- 号
- 3
- 開始ページ
- 535
- 終了ページ
- 542
- 記述言語
- 英語
- 掲載種別
- 研究論文(学術雑誌)
- DOI
- 10.1021/cb2003972
- 出版者・発行元
- AMER CHEMICAL SOC
We report the application of one-dimensional triple-resonance NMR to metabolic analysis and thereon-based evaluation of drug activity. Doubly C-13/N-15-labeled uracil ([(15)N1,(13)C6]-uracil) was prepared. Its catabolic (degradative) conversion to [(13)C3,(15)N4]-beta-alanine and inhibition thereof by gimeracil, a clinical co-drug used with the antitumor agent 5-fluorouracil, in mouse liver lysates were monitored specifically using one-dimensional triple-resonance (H-1-{C-13-N-15}) NMR, but not double-resonance (H-1-{C-13}) NMR, in a ratiometric manner. The administration of labeled uracil to a mouse resulted in its non-selective distribution in various organs, with efficient catabolism to labeled beta-alanine exclusively in the liver. The co-administration of gimeracil inhibited the catabolic conversion of uracil in the liver. In marked contrast to in vitro results, however, gimeracil had practically no effect on the level of uracil in the liver. The potentiality of triple-resonance NMR in the analysis of in vivo pharmaceutical activity of drugs targeting particular metabolic reactions is discussed.
- リンク情報
- ID情報
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- DOI : 10.1021/cb2003972
- ISSN : 1554-8929
- Web of Science ID : WOS:000301515800012