Clinical pharmacokinetics of capecitabine

Capecitabine is a novel oral fluoropyrimidine carbamate that is preferentia lly converted to the cytotoxic moiety fluorouracil (5-fluorouracil; 5-FU) i n target tumour tissue through a series of 3 metabolic steps. After oral ad ministration of 1250 mg/m(2), capecitabine is rapidly and extensively absor bed from the gastrointestinal tract [with a time to reach peak concentratio n (t(max)) of 2 hours and peak plasma drug concentration (C-max) of 3 to 4 mg/L] and has a relatively short elimination half-life (t1/2) [0.55 to 0.89 h]. Recovery of drug-related material in urine and faeces is nearly 100%. Plasma concentrations of the cytotoxic moiety fluorouracil are very low [wi th a Cmax of 0.22 to 0.31 mg/L and area under the concentration-time curve (AUC) of 0.461 to 0.698 mg (.) h/L]. The apparent t1/2 of fluorouracil afte r capecitabine administration is similar to that of the parent compound. Comparison of fluorouracil concentrations in primary colorectal tumour and adjacent healthy tissues after capecitabine administration demonstrates tha t capecitabine is preferentially activated to fluorouracil in colorectal tu mour, with the average concentration of fluorouracil being 3.2-fold higher than in adjacent healthy tissue (p = 0.002). This tissue concentration diff erential does not hold for liver metastasis, although concentrations of flu orouracil in liver metastases are sufficient for antitumour activity to occ ur. The tumour-preferential activation of capecitabine to fluorouracil is e xplained by tissue differences in the activity of cytidine deaminase and th ymidine phosphorylase, key enzymes in the conversion process. As with other cytotoxic drugs, the interpatient variability of the pharmaco kinetic parameters of capecitabine and its metabolites, 5'-deoxy-5-fluorocy tidine and fluorouracil, is high (27 to 89%) and is likely to be primarily due to variability in the activity of the enzymes involved in capecitabine metabolism. Capecitabine and the fluorouracil precursors 5'-deoxy-5-fluoroc ytidine and 5'-deoxy-5-fluorouridine do not accumulate significantly in pla sma after repeated administration. Plasma concentrations of fluorouracil in crease by 10 to 60% during long term administration, but this time-dependen cy is assumed to be not clinically relevant. A potential drug interaction of capecitabine with warfarin has been observe d. There is no evidence of pharmacokinetic interactions between capecitabin e and leucovorin, docetaxel or paclitaxel.