Capecitabine

Gefahreninformationscode (GHS)

• Bildanzeige (GHS)

  

• Alarmwort

  Achtung

• Gefahrenhinweise

  H341：Kann vermutlich genetische Defekte verursachen.

  H350：Kann Krebs verursachen.

• Sicherheit

  P201：Vor Gebrauch besondere Anweisungen einholen.

  P308+P313：BEI Exposition oder falls betroffen: Ärztlichen Rat einholen/ärztliche Hilfe hinzuziehen.

Capecitabine Chemische Eigenschaften,Einsatz,Produktion Methoden

• Beschreibung

  Capecitabine is a new oral fluoropyrimidine carbamate for patients with advanced neoplastic disease, approved as Xeloda for the treatment of refractory metastatic breast cancer after failure on Paclitaxel and an anthracycline-based chemotherapy regimen ; it is a prodrug of doxifluridine (5-fluorouracil ; 5-FU) activated by a cascade of 3 enzymes concentrated in human liver and cancer tissue, resulting in the selective release of 5-FU at the tumor site and offering a prolonged tumour exposure to 5-FU. Oral Capecitabine passes intact through the intestinal mucosa, is converted first by carboxylesterase to 5'-deoxy-5- fluorocytidine in the liver, then by cytidine deaminase to 5'-deoxy-5-fluorouridine in the liver and tumour tissues and finally by thymidine phosphorylase to 5-FU in tumors. Therefore, Xeloda is much safer and more effective than 5-FU (for example, in the HCT116 human colon cancer and the MX-1 breast cancer xenograft .models).

• Chemische Eigenschaften

  Colourless solid

• Originator

  Roche (Switzerland)

• Verwenden

  An antiproliferative 5-fluorouracil releasing compound

• Verwenden

  Capecitabine is an antineoplastic agent. Capecitabine is a prodrug of Doxifluridine (D556750).

• Definition

  ChEBI: A carbamate ester that is cytidine in which the hydrogen at position 5 is replaced by fluorine and in which the amino group attached to position 4 is converted to its N-(penyloxy)carbonyl derivative. Capecitabine is a antineoplastic agen used in the treatment of cancers.

• Manufacturing Process

  5-Deoxy-5-fluoro-N4-((n-pentyloxy)carbonyl)cytidine may be prepared according to US Patent No. 6,114,520.
  From 2',3'-bis-O-(tert-butyldimethylsilyl)-5'-deoxy-5-fluorocytidine and n-pentylchloroformate in dichloromethane and pyridine may be obtained 2',3'- bis-O-(tert-butyldimethylsilyl)-5'-deoxy-5-fluoro-N4-((pentyloxy)carbonyl) cytidine.From 2',3'-bis-O-(tert-butyldimethylsilyl)-5'-deoxy-5-fluoro-N4- ((pentyloxy)carbonyl)cytidineand tetrabutylammonium fluoride in tetrahydrofuran at room temperature for 2 hours may be prepared the product which by hydrolyses may be converted to 5-deoxy-5-fluoro-N4- ((pentyloxy)carbonyl)cytidine. Purification of the product may be carried out by silica gel chromatography (using dichloromethane:methanol = 20:1 as an eluent).

• Trademarks

  Xeloda (Roche).

• Therapeutic Function

  Antitumor

• Allgemeine Beschreibung

  The drug is available in a 150- and 500-mg tablets for oraluse. This drug is a fluoropyrimidine carbamate prodrugform of 5-fluorouracil (5-FU). It is used to treat breast cancerand colorectal cancer. The drug is converted to 5-FU bythe enzyme thymidine phosphorylase following esterase activity to hydrolyze the carbamate moiety and deamination.Capecitabine is readily absorbed by the GI tract, and peakplasma levels of 5-FU occur about 2 hours after oral administration.Indications, drug interactions, and toxicities areequivalent to those of 5-FU.

• Biochem/physiol Actions

  Capecitabine is an anti-cancer drug, a prodrug of doxifluridine, metabolized to 5-fluorouracil at the tumor site. The activation of capecitabine follows a pathway with three enzymatic steps and two intermediary metabolites, 5′-Deoxy-5-fluorocytidine (5′-DFCR) and 5′-Deoxy-5-fluorouridine (5′-DFUR), to form 5-fluorouracil.

• Clinical Use

  Capecitabine is indicated for use as first-line therapy in patients with colorectal cancer. It also is used alone or in combination with docetaxel in patients with metastatic breast cancer who have experienced disease progression or recurrence after anthracycline therapy. Given b.i.d. in tablet form, the total daily dose is calculated based on patient body surface area and is taken 30 minutes after eating to avoid food-induced decreases in absorption. In addition to bone marrow suppression, nausea, and vomiting, the drug can induce severe diarrhea and a potentially disabling disorder termed “hand-and-foot syndrome” (palmar-plantar erythrodysethesia). Capecitabine inhibits CYP2C9 and, along with competition for serum protein binding sites, results in clinically significant drug–drug interactions with both warfarin and phenytoin.

• in vitro

  in antiproliferative assays, both ls174t wt and ls174t-c2 cells were more sensitive to capecitabine when cultivated in the same plates as hepg2 hepatoma. in ls174t wt alone and cultivated with hepg2, ic50values of capecitabine were 890 ± 48 and 630 ± 14 μm respectively. the ic50fell from 330 ± 4 down to 89 ± 6 μmin ls174t-c2 subline when cultivated in the same plates as hepatoma cells.in the ls174t-c2 subclone, whereas little cell death occurred in cells exposed to capecitabine, both early and late apoptosis were increased by 244 and 262%, respectively [1]. furthermore, capecitabine induces apoptosis in a fas-dependent manner, and shows a 7-fold higher cytotoxicity and markedly stronger apoptotic potential in thymidine phosphorylase (tp)-transfected ls174t-c2 cells [2].

• in vivo

  capecitabine was effective in a wider dose range in cxf280, hct116, colo205, and widr human colon cancer xenograft models [2]. in highly metastatic nude mice model, capecitabine inhibited tumor growth and metastatic recurrence after resection of hcc attributed to the high expression of pd-ecgf in tumors [3].

• Arzneimittelwechselwirkung

  Potentially hazardous interactions with other drugs
  Allopurinol: avoid concomitant use.
  Anticoagulants: possibly enhances effect of coumarins.
  Antiepileptics: reported toxicity with fosphenytoin and phenytoin, due to increased phenytoin levels.
  Antipsychotics: avoid with clozapine - increased risk of agranulocytosis.
  Folic acid: toxicity of capecitabine increased - avoid.

• Stoffwechsel

  Although capecitabine is a carbamylated analogue of cytidine , the drug actually is another 5-fluoro-dUMP prodrug. Given orally, it is extensively metabolized to fluorouracil, which is then converted to the active fluorinated deoxyribonucleotide as previously described. Thymidine phosphorylase, an enzyme involved in this biotransformation, is much more active in tumors than in normal tissue, which improves the tumor-selective generation of fluorouracil. Levels of active drug in the tumor can be up to 3.5-fold higher than in surrounding tissue, leading to a lower incidence of side effects compared to fluorouracil therapy. Because capecitabine is biotransformed to fluorouracil, it follows the same catabolic and elimination pathways reported for 5-fluorouracil.

• Lager

  Store at +4°C

• Einzelnachweise

  [1]. ishikawa t, utoh m, sawada n, et al. tumor selective delivery of 5-fluorouracil by capecitabine, a new oral fluoropyrimidine carbamate, in human cancer xenografts[j]. biochemical pharmacology, 1998, 55(7): 1091-1097.
  [2]. ishikawa t, utoh m, sawada n, et al. tumor selective delivery of 5-fluorouracil by capecitabine, a new oral fluoropyrimidine carbamate, in human cancer xenografts[j]. biochemical pharmacology, 1998, 55(7): 1091-1097.
  [3]. zhou j, tang z y, fan j, et al. capecitabine inhibits postoperative recurrence and metastasis after liver cancer resection in nude mice with relation to the expression of platelet-derived endothelial cell growth factor[j]. clinical cancer research, 2003, 9(16): 6030-6037.

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