Takahiro Inaishi1,2, Ken-Ichi Fujita3, Natsumi Matsumoto3, Tomoya Shimokata4, Osamu Maeda4, Toyone Kikumori2, Norifumi Hattori5, Goro Nakayama5, Yuichi Ando4. 1. Department of Clinical Oncology and Chemotherapy, Nagoya University Hospital, Nagoya, Japan t.inaishi@med.nagoya-u.ac.jp. 2. Department of Breast and Endocrine Surgery, Nagoya University Hospital, Nagoya, Japan. 3. Division of Cancer Genome and Pharmacotherapy, Department of Clinical Pharmacy, Showa University School of Pharmacy, Tokyo, Japan. 4. Department of Clinical Oncology and Chemotherapy, Nagoya University Hospital, Nagoya, Japan. 5. Department of Gastroenterological Surgery, Nagoya University Graduate School of Medicine, Nagoya, Japan.
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. Copyright
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. Copyright
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