Capecitabine pharmacokinetics

Tsukamoto Y, Kato Y, Ura M, Horii I, Ishitsuka H, Kusuhara H, Sugiyama Y. A physiologically based pharmacokinetic analysis of capecitabine, a triple prodrug of 5-FU, in humans the mechanism for tumor-selective accumulation of 5-FU. Pharm Res 2001 Aug 18(8) 1190-202. 

Y. Tsukamoto, Y. Kato, M. Ura, I. Horii, H. Ishitsuka, H. Kusuhara, Y. Sugiyama, A physiologically Based Pharmacokinetic Analysis of Capecitabine, a Triple Prodrug of 5-FU, in Humans The Mechanism for Tumor-Selective Accumulation of 5-FU , Pharm. Res. 2001, 18, 1190-1202. 

Fluoropyrimidines (e.g., 5-FU, oral capecitabine) remain unchallenged as reference drugs for treating munerous solid tumors in adults, including digestive, head and neck, and breast cancers. The wide inter-patient variability observed in the pharmacokinetic profiles of these drugs is mainly caused by the erratic activity of dihydropyrimidine... 

As an oral, triple pro-drug, capecitabine has been designed to deliver specifically 5-FU in tumor cells, and as such its pharmacokinetics profile should not be strongly affected by erratic DPD activity in the liver (36). Nevertheless, because the enzymes supporting final activation of capecitabine can be expressed in hepatocytes too, early synthesis of 5-FU may occur in the liver, thus leading eventually to plasma overexposure, as confirmed by a physiologically-based PK model (37). 

Pharmacokinetics Capecitabine is well absorbed following oral administration. It is extensively metabolized to 5-FU (as described above), but also, like uracil, is eventually biotransformed into a-flu-oro-p-alanine. Metabolites are primarily eliminated in the urine. 

R. Gieschke, H. U. Burger, B. Reigner, K. S. Blesch, and J. L. Steimer, Population pharmacokinetics and concentration-effect relationships of capecitabine metabolites in colorectal cancer patients. Br J Clin Pharmacol 55(3) 252-263 (2003). 

Reigner B, Blesch K, Weidekamm E. Chnical pharmacokinetics of capecitabine. Clin Pharmacokinet 2001 40 85-104. 

Cancer research UK pharmacokinetic and pharmacodynamic technologies advisory committee 1250 Candida albicans 1285, 1435 Canferon A 468, 480 Capan-1 1319 Capecitabine 1252... 

Uncertain. However, in a pharmacokinetic study in rats, fluorouracil significantly reduced the total clearance of5-warfarin by inhibiting its metabolism. Data from the clinical study with the fluorouracil prodrug, capecitabine, suggests this interacts similarly. ... 

Studies in patients with refractory advanced cancer have shown that folinic acid 30 mg twice daily does not have a major effect on the pharmacokinetics of capecitabine. However, the pharmacodynamics of capecitabine were affected as determined by the more frequent occurrence of dose-limiting gastrointestinal disorders or hand-foot syndrome. The UK manufacturers say that the maximum tolerated capecitabine dose when used alone in the intermittent regimen is 3000 mg/m, but it is reduced to 2000 mg/m if folinic acid 30 mg twice daily is also given. ... 

There are no clinically significant pharmacokinetic interactions between capecitabine and paclitaxel, and probably not between capecitabine and docetaxel. 

A study in patients with advanced solid tumours found that the use of capecitabine with docetaxel, resulted in an almost twofold decrease in the maximum plasma concentration and AUC of fluorouracil. The authors suggest that more study is needed to assess the significance of this finding. Other pharmacokinetic parameters of capecitabine were not affected by docetaxel, and the pharmacokinetics of docetaxel were not significantly affected by capecitabine or its metabolites. ... 

Other studies in similar patients also found that capecitabine did not alter the pharmacokinetics of docetaxel and that the concurrent use of paclitaxel and capecitabine did not significantly alter the pharmacokinetics of either drug. ... 

Pharmacokinetics After oral administration, capecitabine passes unchanged through the intestinal tract. It is rapidly and extensively absorbed, with a t ,ax of 1-2 hours. The speed and extent of absorption are reduced by food. The half-life is 0.6 hours. Excretion of capecitabine and its metabolites is almost completely via the urine and occurs within 24 hours of dosing [98. ... 

Judson IR, Beale PJ, Trigo JM, Aherne W, Crompton T, Jones D, Bush E, Reigner B. A human capecitabine excretion balance and pharmacokinetic study after administration of a single oral dose of C-labelled drug. Invest New Drugs 1999 17(1) 49-56. 

Reigner, B. Verweij, J. Dirix, L. Cassidy, J. Twelves, C. Allman, D. Weidekamm, E. Rods, B. Banken, L. Utoh, M. Osterwalder, B. Effect of food on the pharmacokinetics of capecitabine and its metabohtes following oral administration in cancer patients, Clin.Cancer Res., 1998, 4, 941-948. 

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