Capecitabine activation pathway enzymes

The capecitabine activation pathway enzymes comprise a three-step metabolic cascade responsible for converting the oral prodrug capecitabine into its active cytotoxic form, 5-fluorouracil (5-FU) [6, 10]. This pathway is designed to achieve tumor-selective drug delivery by exploiting the differential expression of enzymes between healthy and malignant tissues. The process begins in the liver, where carboxylesterases (primarily CES1 and CES2) hydrolyze capecitabine to 5'-deoxy-5-fluorocytidine (5'-DFCR) [4, 10]. Subsequently, cytidine deaminase (CDA), present in the liver and various tumor types, converts 5'-DFCR into 5'-deoxy-5-fluorouridine (5'-DFUR) [6, 10]. The final and most critical step is the conversion of 5'-DFUR to 5-FU by thymidine phosphorylase (TP), an enzyme that is significantly overexpressed in many solid tumors, thereby concentrating the active drug at the site of the disease [5, 12]. This enzymatic system is a key determinant of the therapeutic index of capecitabine in treating colorectal, breast, and gastric cancers [12, 13]. Clinical outcomes and safety are further influenced by the catabolic enzyme dihydropyrimidine dehydrogenase (DPD), whose deficiency can lead to life-threatening toxicity due to impaired 5-FU clearance [1, 18].

Other names

Capecitabine bioactivation pathway5-FU activation pathwayCarboxylesterase/Cytidine deaminase/Thymidine phosphorylase pathway

Sequential enzymatic conversion of the prodrug capecitabine into the active cytotoxic agent 5-fluorouracil (5-FU) through hydrolysis by carboxylesterase, deamination by cytidine deaminase, and phosphorolysis by thymidine phosphorylase.