Capecitabine metabolism

Y.L. Chung, H. Troy, I.R. Judson, R. Leek, M.O. Leach, M. Stubbs, A.L. Harris, J.R. Griffiths, Noninvasive measurements of capecitabine metabolism in bladder tumors overexpressing thymidine phosphorylase by fluorine-19 magnetic resonance spectroscopy, Clin. Cancer Res. 10 (2004) 3863-3870. 

Source Klomp D, van Laarhoven FL, Scheenen F, Kamm Y, LLeerschap A., Quantitative 191 MR spectroscopy at 3T to detect heterogeneous capecitabine metabolism in human liver, NMR in Biomedicine (2007) 20, 485-492. Copyright (2007) John Wiley Sons. Reprinted with permission.)... 

The recent availability of oral formulations of 5-FU involving the ability to modulate the anabolic and catabolic metabolism of 5-FU with LV and dihydropyrimidine dehydrogenase (DPD) inhibitors has provided a substantial improvement in the ease of administration and may probably improve the efficacy of fluoropyrimidine-induced radiosensitization. Such oral fluoropyrimidines include UFT (uracil tegafur) plus oral LV (Orzel ), an oral DPD-inhibitory fluoropyrimidine (DIF), and capecitabine (Xeloda Roche). 

Fig. IB. Metabolic pathway of the oral pro-drug capecitabine. The dmg has been designed to generate specifically 5-FU in tumor cells over-expressing thymidine phosphorylase.

Capecitabine is a fluoropyrimidine carbamate prodrug with 70-80% oral bioavailability. It undergoes extensive metabolism in the liver by the enzyme carboxylesterase to an intermediate, 5 -deoxy-5-fluorocytidine. This is converted to 5 -deoxy-5-fluorouridine by the enzyme cytidine deaminase. These two initial steps occur mainly in the liver. The 5 -deoxy-5-fluorouridine metabolite is then hydrolyzed by thymidine phosphorylase to 5-FU directly in the tumor. The expression of thymidine phosphorylase has been shown to be significantly higher in a broad range of solid tumors than in corresponding normal tissue, particularly in breast cancer and colorectal cancer. 

The in vivo metabolism of capecitabine (1) to the active tumor cytotoxic substance 5-fluorouracil (5) is now fairly well understood. When capecitabine is administered orally it is delivered to the small intestine, where it is not a substrate for thymidine phosphorylase in intestinal tissue, and so passes through the intestinal mucosa as an intact molecule and into the bloodstream. When 1 reaches the liver, the carbamate moiety is hydrolyzed through the action of carboxylesterase enzymes, liberating 5 -deoxy-5-fluorocytidine (5 -DFCR, 10). DFUR is partially stable in systemic circulation, but eventually diffuses into tumor cell tissue where it is transformed into 5 -deoxy-5-fluorouridine (5 -DFUR, 9) by cytidine deaminase, an enzyme present in high concentrations in various types of human cancers compared to adjacent healthy cells (although it is present in significantly lower levels in the liver). Within the tumor, 5-... 

Metabolic pathway of capecitabine to 5-FU. 5-DFCR = 5 -deoxy-5-fluoro-cytidine 5-DFUR = 5 -deoxy-5-fluorouridine... 

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. 

Capecitabine is metabolized to fluorouracil >- Flurorouracil/capecitabine, below ... 

CAPECITABINE ANTIGOUT DRUGS-ALLOPURINOL Possible 1 efficacy of capecitabine Capecitabine is a prodrug for fluorouracil it is uncertain at which point allopurinol acts on the metabolic pathway Manufacturers recommend avoiding co-administration... 

The toxicity of antimetabolites is, as expected, due to their incorporation into the metabolism of normal cells, which is nearly identical to that of the malignant cells that they were designed to injure. The normal cells injured most severely are the rapidly proliferating cells of the bone marrow, the lymphoid system, and the GI epithelium. Thus, the common toxicities are bone marrow depression, nausea and vomiting, diarrhea, and mucositis. Cytarabine and pentostatin can cause conjunctivitis. Capecitabine and prolonged use of fluorouracil or cytarabine can cause cerebellar ataxia and the hand-foot syndrome, that is, palmar-plantar erythrodysesthesia or acral erythema. Pentostatin and high-dose methotrexate can cause renal toxicity. 

In addition to 5-FU, its fluorinated prodrugs such as gemzar, floxuridine, capecitabine, tegafur uracil, etc. have also been evaluated using 19F MR spectroscopy, at least in the laboratory or in animal models [3, 7-10], Improved efficacy of 5-FU has been achieved by using it in combination with other medications that either modulate its uptake or/and increase its metabolism. 19F MR has been used to measure the modulation of 5-FU... 

Figure 13.44. Metabolic activation of capecitabine (50), a site-selective multistep prodrug of the antitumor drug 5-fluorouracil (5-FU) (53)Following oral absorption, the prodrug is hydrolyzed by liver carboxylesterase to a carbamic acid that spontaneously decarboxylates to 5 -deow-5-fluorocy-tidine (51). The latter is transformed into 5 -deoxy-5-fluorouridine (52) by cytidine deaminase present in the liver and tumors. The third activation step occurs selectively in tumor cells and involves the transformation to 5-FU (53), catalyzed by thymidine phosphorylase (221).

The kinetics of 5-fluorouracil and its metabolites are essentially nonlinear. Therefore it is extremely difficult to build models that would correctly describe the cascade of nonlinear transformations that are observed, starting from drug absorption to its transformation into the active moiety. More recently, capecit-abine has been commercialized. It is a fluor-pyrimidine carbamate available for oral administration. Concentrations of 5-fluorouracil in some tumors are higher than those in the adjacent healthy tissues. The tumor preferential activation of capecitabine to 5-fluorouracil is explained by tissue differences in the activity of cytidine deaminase and thymidine phos-phorylase. It is interesting to note that the last of the three metabolic steps leading to 5-fluorouracil is the formation of 5 -deoxy-5-fluori-dine. Capecitabine is thus a pro-prodrug (176-178). 

Capecitabine is a pyrimidine analog. It is an oral systemic prodrug that is enzymatically converted to 5-fluorouracil (5-FU). Healthy and tumor cells metabolize 5-FU to 5-fluoro-2-deoxyuridine monophosphate (FdUMP) and 5-flu-orouridine triphosphate (FUTP). These metabolites cause cell injury by two different mechanisms. First, they inhibit the formation of thymidine triphosphate, which is essential for the synthesis of DNA. Second, nuclear transcriptional enzymes can mistakenly incorporate FUTP during the synthesis of RNA. This metabolic error can interfere with RNA processing and protein synthesis. Capecitabine is indicated in the treatment of resistant metastatic breast cancer alone or in combination with docetaxel, and colorectal cancer. 

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. ... 

Desmoulin F, Gilard V, Mtdet-Martino M, Martino R (2002) Metabolism of capecitabine, an oral iluoroiiracil prodrug F NMR studies in animal models and human urine. Drug Metab Dispos 30 1221-1229... 

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