A physiologically based pharmacokinetic analysis of capecitabine, a tripleprodrug of 5-FU, in humans: The mechanism for tumor-selective accumulationof 5-FU

Purpose. To identify the factors governing the dose-limiting toxicity in th e gastrointestine (Gl) and the antitumor activity after oral administration of capecitabine, a triple prodrug of 5-FU, in humans. Method. The enzyme kinetic parameters for each of the four enzymes involved in the activation of capecitabine to 5-FU and its elimination were measure d experimentally in vitro to construct a physiologically based pharmacokine tic model. Sensitivity analysis for each parameter was performed to identif y the parameters affecting tissue 5-FU concentrations. Results. The sensitivity analysis demonstrated that (i) the dihydropyrimidi ne dehydrogenase (DPD) activity in the Ever lar.-cly determines the 5-FU AU C in the systemic circulation, (ii) the exposure of tumor tissue to 5-FU de pends mainly on the activity of both thymidine phosphorylase (dThdPase) and DPD in the tumor tissues, as well as the blood flow rate in tumor tissues with saturation of DPD activity resulting in 5-FU accumulation, and (iii) t he metabolic enzyme activity in the GI and the DPD activity in liver are th e major determinants influencing exposure to 5-FU in the GI. The therapeuti c index of capecitabine was found to be at least 17 times greater than that of other 5-FU-related anticancer agents, including doxifluridine, the prod rug of 5-FU, and 5-FU over their respective clinical dose ranges. Conclusions. It was revealed that the most important factors that determine the selective production of 5-FU in tumor tissue after capecitabine admini stration are tumor-specific activation by dThdPase, the nonlinear eliminati on of 5-FU by DPD in tumor tissue, and the blood flow rate in tumors.