Figure 1.

Capecitabine activation and subsequent 5-FU activation, action, transport and catabolism. Capecitabine is an oral 5-FU prodrug that is rationally designed so that concentrations of the cytotoxic metabolites FdUMP, FdUTP and FUTP are higher within malignant cells than within normal cells. After absorption in the gut, most of the drug activation occurs via the common pro-drug activation route (a), starting in the liver and finishing in the tumour. Additionally, 5-FU can be converted to its active compounds via alternate activation routes (b) in colon tumour cells and cells from multiple other tissues. Toxicity may occur if non-target tissue is exposed to activated capecitabine/5-FU (ie, FdUMP, FdUTP and FUTP), either when 5-FU is activated prior to arrival at the tumour or when it exits target tissue and is subsequently activated. 5-FU released in circulation may be quickly metabolised (c) in the liver by enzymes including DPYD. Gene names for candidate enzymes, provided in circles, are defined in online supplementary table S1. Drug catabolites are provided in rectangles. Primary (rationally designed) pathway are shown in solid lines, and alternative pathways shown in dashed lines.