Investigation of 5-FU disposition after oral administration of capecitabine, a triple-prodrug of 5-FU, using a physiologically based pharmacokinetic model in a human cancer xenograft model: Comparison of the simulated 5-FU exposures in the tumour tissue between human and xenograft model

The nonlinear pharmacokinetics of capecitabine, a triple prodrug of 5-FU pr eferentially activated in tumour tissues, was investigated in human cancer xenograft models. A physiologically based pharmacokinetic (PBPK) model inte grating the activation process of capecitabine to 5-FU and 5-FU elimination was constructed to describe the concentration/time profiles of capecitabin e and its three metabolites, including 5-FU, in blood and organs. All the b iochemical parameters (enzyme kinetic parameters, plasma protein binding an d tissue binding of capecitabine and its metabolites) integrated in this mo del were measured in vitro. The simulated curves for the blood and tumour c oncentrations of capecitabine and its metabolites can basically describe th e observed values. A simple prodrug of 5-FU, doxifluridine, is known to be activated to 5-FU to some extent in the gastrointestinal (GI) tract, causin g diarrhoea, which is the dose limiting side effect of doxifluridine. Conse quently, the therapeutic index (the ratio of 5-FU AUC in the tumour to that in GI) after the administration of effective dose capecitabine was predict ed by this PBPK model and found to be five times and 3000 times greater tha n that of doxifluridine and 5-FU, respectively. This was compatible with th e previous result for the difference in the ratio of the toxic dose to the minimum effective dose between capecitabine and doxifluridine, suggesting t hat 5-FU preferentially accumulates in tumour tissue after oral administrat ion of capecitabine compared with the other drugs (doxifluridine and 5-FU). The 5-FU AUC in tumour tissue of human cancer xenograft models at the mini mum effective dose was comparable with those estimated for humans at the cl inical dose. In addition, the predicted therapeutic indices at the respecti ve doses were correlated well between humans and mice (xenograft model). Th ese results suggest that the 5-FU AUC in human tumour tissue at its clinica lly effective dose can be predicted based on the PBPK model inasmuch as the 5-FU AUC in a human cancer xenograft model at its effective dose may be me asured or simulated. Copyright (C) 2001 John Wiley & Sons, Ltd.