High-throughput screening of potential inhibitors for the metabolism of the investigational anti-cancer drug 5,6-dimethylxanthenone-4-acetic acid

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• 作者：Zhou ; Shufeng ; Chiang ; Daniel ; Chin ; Rebecca ; Kestell ; Philip ; Paxton ; James W.
• 刊名：Journal of Chromatography B, Analytical Technologies in the Biomedical and Life Sciences
• 出版年：2002
• 出版时间：February 5, 2002
• 年：2002
• 卷：767
• 期：1
• 页码：19-26
• 全文大小：109 K

文摘

By screening potential inhibitors of drug metabolism using the in vitro models, potential drug–drug interactions in vivo may be predicted with the use of appropriate pharmacokinetic principles. This study aimed to develop a rapid screening system using human liver microsomes to efficiently identify the potential inhibitors of DMXAA metabolism. Initial IC₅₀ was estimated by using a two-point method, and then K_i values were determined if required and compared with those initial IC₅₀ values. More than 100 compounds including known substrates and inhibitors of human uridine diphosphate glucuronosyltransferases (UGTs) and cytochrome P450 (CYP), anti-cancer drugs and xanthenone analogues were screened for their inhibitory effect on DMXAA glucuronidation and 6-methylhydroxylation in human liver microsomes. Both metabolites of DMXAA, DMXAA acyl glucuronide (DMXAA-G) and 6-hydroxymethyl-5-methylxanthenone-4-acetic acid (6-OH-MXAA), formed in human liver microsomes were quantitated by validated HPLC methods. The results indicated that there was a significant relationship (r²