[Pharmacokinetic comparison of capecitabine and 5'-deoxy-5-fluorouridine (doxifluridine; 5'-DFUR)]

Capecitabine is a new oral fluoropyrimidine derivative. It is a prodrug that is activated to fluorouracil in three metabolic steps. Compared to 5'-deoxy-5-fluorouridine (doxifluridine) itself, capecitabine was designed to deliver more doxifluridine to cancer cells,where it is activated to fluorouracil. Based on differential distribution of the three metabolizing enzymes in different tissues, capecitabine is considered to yield more fluorouracil in cancer cells than bone marrow cells or gastro-intestinal epithelial cells. Due to these pharmacokinetic merits, capecitabine can be given at a higher dose, and therefore is expected to yield higher antitumor activity, than doxifluridine. To investigate the pharmacokinetic advantage of capecitabine compared to doxifluridine, pharmacological studies of both drugs have been conducted in phase II trials. These used the same study design,and compared the pharmacokinetics and pharmacodynamics between capecitabine and doxifluridine. The area under the curve of doxifluridine was 2.3 times higher after the administration of capecitabine than doxifluridine, suggesting that higher intratumor concentrations of fluorouracil were indeed achieved after capecitabine administration. This study clearly documents the pharmacokinetic superiority of capecitabine compared to doxifluridine.