Variants ofcarboxylesterase 1have no impact on capecitabine pharmacokinetics and toxicity in capecitabine plus oxaliplatin treated-colorectal cancer patients

Purpose Capecitabine is a prodrug that undergoes metabolism in three steps to form an active 5-fluorouracil (5-FU). The first step is primarily catalyzed by liver carboxylesterases (CES) 1. Here, we examined the effects ofCES1variants on pharmacokinetics and toxicity of capecitabine. Methods We enrolled postoperative colorectal cancer (CRC) patients administered with adjuvant capecitabine plus oxaliplatin (CapeOX) and metastatic CRC patients receiving CapeOX. The pharmacokinetic analysis of the first capecitabine dose (1000 mg/m(2)) was done on day 1, and oxaliplatin administration was shifted to day 2. Plasma concentrations of capecitabine, 5 '-deoxy-5-fluorocytidine, 5 '-deoxy-5-fluorouridine (5 '-DFUR), and 5-FU were analyzed by high-performance liquid chromatography.CES1polymorphisms (rs3217164, rs2244614, rs2244613, rs7187684, and rs11861118) and the functionalCES1genes (1A1,var1A1,1A2, and pseudo1A3) in their diplotype configurations were analyzed by direct sequencing. Results Thirty-seven patients were enrolled from September 2017 to February 2020. Patients with a higher area under the plasma concentration-time curve to capecitabine dose ratio (AUC/dose) of 5 '-DFUR than its mean showed a higher frequency of overall >= grade 3 toxicity and lower relative dose intensity (RDI) of capecitabine than those with a lower ratio. Higher CES1 activity expressed as a metabolic ratio (AUC of capecitabine/sum of three AUCs of each metabolite) lower than its mean was associated with higher 5 '-DFUR AUC/dose and lower RDI, indicating essential roles of CES1 in capecitabine activation to produce 5 '-DFUR. However, the association betweenCES1variants and capecitabine pharmacokinetics and toxicity was not significant. Conclusion CES1variants are not associated with capecitabine pharmacokinetics and toxicity.