Titre du document / Document title

Clinical pharmacokinetics of capecitabine

Auteur(s) / Author(s)

REIGNER Bruno ⁽¹⁾ ; BLESCH Karen ⁽²⁾ ; WEIDEKAMM Erhard ⁽¹⁾ ;

Affiliation(s) du ou des auteurs / Author(s) Affiliation(s)

⁽¹⁾ Pharma Development, F. Hoffmann-La Roche Ltd, Basel, SUISSE
⁽²⁾ Pharma Development, Hoffmann-La Roche Inc., Nutley, New Jersey, ETATS-UNIS

Résumé / Abstract

Capecitabine is a novel oral fluoropyrimidine carbamate that is preferentially converted to the cytotoxic moiety fluorouracil (5-fluorouracil; 5-FU) in target tumour tissue through a series of 3 metabolic steps. After oral administration of 1250 mg/m², capecitabine is rapidly and extensively absorbed from the gastrointestinal tract [with a time to reach peak concentration (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 0.89h]. Recovery of drug-related material in urine and faeces is nearly 100%. Plasma concentrations of the cytotoxic moiety fluorouracil are very low [with a C_max 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 after 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 that capecitabine is preferentially activated to fluorouracil in colorectal tumour, with the average concentration of fluorouracil being 3.2-fold higher than in adjacent healthy tissue (p = 0.002). This tissue concentration differential does not hold for liver metastasis, although concentrations of fluorouracil in liver metastases are sufficient for antitumour activity to occur. The tumour-preferential activation of capecitabine to fluorouracil is explained by tissue differences in the activity of cytidine deaminase and thymidine phosphorylase, key enzymes in the conversion process. As with other cytotoxic drugs, the interpatient variability of the pharmacokinetic parameters of capecitabine and its metabolites, 5'-deoxy-5-fluorocytidine 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-fluorocytidine and 5'-deoxy-5-fluorouridine do not accumulate significantly in plasma after repeated administration. Plasma concentrations of fluorouracil increase by 10 to 60% during long term administration, but this time-dependency is assumed to be not clinically relevant. A potential drug interaction of capecitabine with warfarin has been observed. There is no evidence of pharmacokinetic interactions between capecitabine and leucovorin, docetaxel or paclitaxel.

Revue / Journal Title

Clinical pharmacokinetics   ISSN 0312-5963   CODEN CPKNDH 

Source / Source

2001, vol. 40, n^o2, pp. 85-104 (58 ref.)

Langue / Language

Anglais

Editeur / Publisher

Adis international, Auckland, NOUVELLE-ZELANDE  (1976) (Revue)

Mots-clés anglais / English Keywords

Capecitabine ; Fluorouracil ; Prodrug ; Pharmacokinetics ; Human ; Review ; Oral administration ; Drug combination ; Drug interaction ; Food drug interaction ; Antineoplastic agent ; Metabolism ; Metabolite ; Fluoropyrimidine derivatives ; Pyrimidine derivatives ;

Mots-clés français / French Keywords

Capécitabine ; Fluorouracil ; Promédicament ; Pharmacocinétique ; Homme ; Article synthèse ; Voie orale ; Association médicamenteuse ; Interaction médicamenteuse ; Interaction aliment médicament ; Anticancéreux ; Métabolisme ; Métabolite ; Fluoropyrimidine dérivé ; Pyrimidine dérivé ;

Mots-clés espagnols / Spanish Keywords

Capecitabina ; Fluorouracilo ; Promedicamento ; Farmacocinética ; Hombre ; Artículo síntesis ; Vía oral ; Asociación medicamentosa ; Interacción medicamentosa ; Interacción alimento medicamento ; Anticanceroso ; Metabolismo ; Metabolito ; Fluoropirimidina derivado ; Pirimidina derivado ;

Localisation / Location

INIST-CNRS, Cote INIST : 15599, 35400009807786.0020