Indications
Capecitabine is a chemotherapeutic agent indicated for the treatment of various cancer types. For colorectal cancer, it is utilized either as a monotherapy or as part of a combination regimen for the adjuvant treatment of stage III colon cancer, as well as for unresectable or metastatic cases. It is also employed in combination chemotherapy for the perioperative management of adult patients with locally advanced rectal cancer. In the context of breast cancer, capecitabine serves as a monotherapy for advanced or metastatic disease when an anthracycline- or taxane-based therapy is unsuitable, or in combination with docetaxel following disease progression post-anthracycline therapy. For gastric, esophageal, or gastroesophageal junction cancers, capecitabine forms part of a combination regimen to treat adult patients with unresectable or metastatic disease, including those with HER2-positive metastatic gastric or gastroesophageal junction adenocarcinoma who have not previously been treated for metastasis. Additionally, in pancreatic cancer, it is prescribed as part of the adjuvant treatment regimen for adult pancreatic adenocarcinoma.
Pharmacodynamics
Capecitabine is a fluoropyrimidine carbamate and is categorized under antimetabolites, which are specifically designed to eradicate cancer cells by disrupting DNA synthesis. Administered orally, it is a prodrug that exhibits minimal pharmacologic activity until its conversion to 5-fluorouracil (5-FU) via tumor-expressed enzymes. Capecitabine's design intends to circumvent the limitations of 5-FU while simulating its infusion pharmacokinetics, eliminating the need for complex central venous access and infusion devices. This is significant because gastrointestinal toxicity and reduced efficacy are associated with 5-FU intravenous infusion. The capability of capecitabine to be absorbed intact across the intestinal lining allows for a targeted delivery of 5-FU to tumorous tissues, facilitated by selective enzymatic conversion. The active metabolite, 5-FU, functions by inhibiting thymidylate synthase, DNA, and RNA, thus inducing protein synthesis interruption and apoptosis. Studies have shown a correlation between the concentration of 5-FU in the body and the occurrence of grade 3-4 hyperbilirubinemia.
Absorption
Upon administration, the Area Under Curve (AUC) for capecitabine and its metabolites, including 5'-DFCR, ascends proportionally with doses ranging from 500 mg/m²/day to 3,500 mg/m²/day. However, the AUC for metabolites 5'-DFUR and fluorouracil increases more than dose-proportionally, with notable variability (over 85%) observed in the Cmax and AUC values of fluorouracil between different patients. When administered orally at a dose of 1,255 mg/m² twice daily, which is the recommended dosage for monotherapy, capecitabine and its metabolite fluorouracil reach their peak blood levels at a median time (Tmax) of approximately 1.5 and 2 hours, respectively.
Metabolism
Capecitabine undergoes metabolic conversion through several enzymatic steps. Initially, the carboxylesterase enzyme catalyzes the hydrolysis of capecitabine to 5'-DFCR. Subsequently, cytidine deaminase converts 5'-DFCR to 5'-DFUR, which is then hydrolyzed by thymidine phosphorylase (dThdPase), resulting in the active metabolite, fluorouracil. Fluorouracil is further metabolized by dihydropyrimidine dehydrogenase to yield 5-fluoro-5,6-dihydro-fluorouracil (FUH2). Following this, dihydropyrimidinase cleaves the FUH2 pyrimidine ring to produce 5-fluoro-ureido-propionic acid (FUPA), which is subsequently broken down by β-ureido-propionase, leading to the formation of α-fluoro-β-alanine (FBAL).
Mechanism of Action
Capecitabine undergoes in vivo conversion to 5-fluorouracil (5-FU) through a series of enzymatic steps involving carboxylesterases, cytidine deaminase, and thymidine phosphorylase/uridine phosphorylase. The resulting 5-FU is further metabolized into three primary active metabolites: 5-fluorouridine triphosphate (5-FUTP), 5-fluoro-2'-deoxyuridine monophosphate (5-FdUMP), and 5-fluorodeoxyuridine triphosphate (5-FdUTP). These metabolites exert cytotoxic effects through two distinct mechanisms. Firstly, FdUMP interacts with the folate cofactor, N5-10-methylenetetrahydrofolate, to form a covalently bound ternary complex with thymidylate synthase (TS), an enzyme responsible for the conversion of deoxyuridine monophosphate (dUMP) to deoxythymidine monophosphate (dTMP). Normally, dUMP binds to TS, allowing for successful methylation. However, substitution with FdUMP leads to the formation of a time-dependent TS-FdUMP-CH2THF complex. The irreversibility of this complex due to the fluorine group's presence results in "suicide inhibition," thereby halting the conversion of dUMP to dTMP. This disruption leads to a depletion of dTMP, impairing DNA synthesis and repair, which ultimately induces apoptosis. Moreover, FdUMP can be phosphorylated into FdUTP, which, along with a decrease in dTTP, increases the likelihood of uracil being mistakenly incorporated into DNA. Although nucleotides are usually corrected by uracil-DNA-glycosylase, an elevated (F)dUTP/dTTP ratio perpetuates a cycle of misincorporation and repair, causing DNA mutagenesis, replication fork collapse, and potential DNA fragmentation. Despite these disruptions, studies indicate that 5-FU's cytotoxicity is predominantly due to RNA perturbation, mediated by 5-FUTP. This active metabolite can be erroneously incorporated into RNA, affecting RNA biology by altering spliceosomal RNA processing and tRNA modifications. Recent findings also suggest that 5-FUTP affects microRNAs and long non-coding RNAs, though the underlying mechanisms remain unclear. Importantly, 5-FU shows significant accumulation in RNA, influencing RNA biology more than DNA, and highlighting the central role of RNA-mediated mechanisms in 5-FU's pharmacological action.
