Celabin Mechanism of Action

Pharmacologic Classification: Cytostatic (Antimetabolite).
Pharmacology: Mechanism of Action: Capecitabine is a tumor-activated antineoplastic agent (antimetabolite) belonging to the novel fluoropyrimidine carbamate class. It is an orally administered prodrug of 5'-deoxy-5-fluorouridine (5'-DFUR) which is converted to 5-fluorouracil (5-FU). Enzymes convert capecitabine to 5-FU in vivo. Both normal and tumor cells metabolize 5-FU to 5-fluoro-2'-deoxyuridine monophosphate (FdUMP) and 5-fluorouridine triphosphate (FUTP). These metabolites cause cell injury by two different mechanisms. First, FdUMP and the folate cofactor N^5-10-methylenetetrahydrofolate bind to thymidylate synthase (TS) to form a covalently bound ternary complex. This binding inhibits the formation of thymidylate from 2'-deoxyuridylate. Thymidylate is the necessary precursor of thymidine triphosphate, which is essential for the synthesis of DNA, so that a deficiency of this compound can inhibit cell division. Second, nuclear transcription enzymes can mistakenly incorporate FUTP in place of uridine triphosphate (UTP) during the synthesis of RNA. This metabolic error can interfere with RNA processing and protein synthesis.
In a large randomized trial, combination of docetaxel and capecitabine produces a synergistic antitumor effect for the treatment of advanced breast cancer.
Bioavailability and Pharmacokinetics: Capecitabine is rapidly and extensively absorbed unchanged from the gastrointestinal (GI) tract; on average at least 70% of an oral dose is absorbed. After oral administration of 1255 mg/m2 two times a day to cancer patients, capecitabine reached peak blood levels in about 1.5 hours (T_max) with peak 5-FU levels occurring slightly later, at 2 hours. Food reduced both the rate and extent of absorption of capecitabine with mean peak plasma concentration (C_max) and area under the concentration-time curve (AUC_0-∞) decreased by 60% and 35%, respectively. The C_max and AUC_0-∞ of 5-FU were also reduced by food by 43% and 21%, respectively. Food delayed T_max of both parent and f-FU by 1.5 hours.
The pharmacokinetics of capecitabine and its metabolites have been evaluated over a dose range of 500 to 3500 mg/m²/day. Over this range, the pharmacokinetics of capecitabine and its metabolite, 5'-deoxy-5-fluorocytidine (5'- DFCR) were dose proportional and did not change over time. The increases in the AUCs of 5'-DFUR and 5-FU, however, were greater than proportional to the increase in dose and the AUC of 5-FU was 34% higher on day 14 than on day 1.
Plasma protein binding of capecitabine and its metabolites is <60% and is not concentration dependent. Capecitabine is primarily bound to human albumin (~35%). Capecitabine has a low potential for pharmacokinetic interactions related to plasma protein binding.
Capecitabine has little pharmacologic activity until it is extensively metabolized enzymatically to 5-FU. In the liver, much of the compound is hydrolyzed by a 60 kDa carboxylesterase to 5'-DFCR. Cytidine deaminase, principally located in the liver and tumor tissue, subsequently converts 5'-DFCR to 5'-DFUR. Further metabolism of 5'-DFUR to the pharmacologically active agent 5-FU occurs mainly at the site of the tumor by thymidine phosporylase (dThdPase), which has levels considerably higher in tumor tissues compared to normal tissues.
The enzyme dihydropyrimidine dehydrogenase hydrogenates 5-FU, the product of capecitabine metabolism to the much less toxic 5-fluoro-5,6-dihydro-fluorouracil (FUH₂). Dihydropyrimidinase cleaves to the pyrimidine ring to yield 5-fluoroureido- propionic acid (FUPA). Finally, β-ureido-propionase cleaves FUPA to α-fluoro-β-alanine (FBAL) which is cleared in the urine.
Capecitabine and its metabolites are predominantly excreted in the urine; 95.5% of administered capecitabine dose is recovered in urine. Fecal excretion is minimal (2.6%). The major metabolite excreted in urine is FBAL which represents 57% of the administered dose. About 3% of the administered dose is excreted in urine as unchanged drug. The elimination half-life of both parent capecitabine and 5-FU was about 0.75 hour.