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

Abstract

Aim: 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 and methods: Patients with colorectal cancer who received capecitabine plus oxaliplatin were selected. Pharmacokinetics of capecitabine and its metabolites, and CDA activity in plasma were analyzed.

Results: 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.

Conclusion: Metabolism of 5'-DFCR to form 5'-DFUR increased as CLcr decreased but the mechanism remains unknown.

Keywords: 5’-DFCR; 5’-DFUR; capecitabine; creatinine clearance; cytidine deaminase.