Correlation Between the Metabolic Conversion of a Capecitabine Metabolite, 5'-Deoxy-5-fluorocytidine, and Creatinine Clearance.

Abstract

Capecitabine is a prodrug that is metabolized to its active form, 5-fluorouracil (5-FU), in three enzymatic steps. This prospective pharmacokinetic study evaluated cytidine deaminase (CDA) activity, the second drug-metabolizing enzyme that generates 5'-deoxy-5-fluorouridine (5'-DFUR) from 5'-deoxy-5-fluorocytidine (5'-DFCR), as well as creatinine clearance (CLcr). Patients with colorectal cancer who received capecitabine plus oxaliplatin were selected. Pharmacokinetics of capecitabine and its metabolites, and CDA activity in plasma were analyzed. Eighteen patients were examined. The area under the plasma concentration-time curve (AUC) of 5'-DFUR showed a significant inverse correlation with CLcr (p=0.003). The metabolic ratio, i.e. the ratios of the AUC of 5'-DFUR plus that of 5-FU to the AUC of 5'-DFCR, significantly increased when CLcr decreased (p=0.001) but did not depend on plasma CDA activity. Metabolism of 5'-DFCR to form 5'-DFUR increased as CLcr decreased but the mechanism remains unknown.