著者

杉山 雄一 塚本 友子 堀井 郁夫

出版者

The Japanese Society for the Study of Xenobiotics

雑誌

薬物動態 (ISSN:09161139)

巻号頁・発行日

vol.16, no.supplement, pp.84-85, 2001-09-17 (Released:2007-03-29)

参考文献数

2

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Capecitabine, an orally administered triple prodrug of 5-FU shows tumor-preferential exposure of 5-FU by being sequentially metabolized to 5-FU by three enzymes, which show relatively specific organ expression. To investigate the mechanism of tumor-preferential exposure of 5-FU after oral administration of capecitabine, a physiologically based pharmacokinetic model describing the pharmacokinetic behaviors of capecitabine and its metabolites including 5-FU in humans was constructed. The factors that have the greatest influence on the pharmacokinetics of 5-FU after administration of capecitabine were clarified by sensitivity analyses. The sensitivity analysis demonstrated the exposure of tumor tissue to 5-FU depends mainly on the activity of both thymidine phosphorylase (producing enzyme of 5-FU from the precursor, 5'-DFUR) and DPD (eliminating enzyme of 5-FU) in tumor tissue, as well as blood flow rate in tumor tissue with saturation of DPD activity resulting in higher 5-FU AUC in tumor tissue. The therapeutic index of capecitabine was found to be at least 17 times greater than that of other fluoropyrimidine, including doxifluridine, the prodrug of 5-FU, and 5-FU over their respective clinical dose ranges.