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 of CES1 variants 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/m²) 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. CES1 polymorphisms (rs3217164, rs2244614, rs2244613, rs7187684, and rs11861118) and the functional CES1 genes (1A1, var1A1, 1A2, and pseudo 1A3) 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 between CES1 variants and capecitabine pharmacokinetics and toxicity was not significant.

Conclusion

CES1 variants are not associated with capecitabine pharmacokinetics and toxicity.

中文翻译：

---

羧酸酯酶1的变体对卡培他滨加奥沙利铂治疗的结直肠癌患者的卡培他滨药代动力学和毒性没有影响。

目的

卡培他滨是一种前药，它通过三个步骤进行代谢以形成活性的5-氟尿嘧啶（5-FU）。第一步主要由肝羧酸酯酶（CES）1催化。在这里，我们检查了CES1变体对卡培他滨的药代动力学和毒性的影响。

方法

我们招募了接受卡培他滨联合奥沙利铂（CapeOX）辅助治疗的术后结直肠癌（CRC）患者和接受CapeOX的转移性CRC患者。在第1天进行第一个卡培他滨剂量（1000 mg / m ²）的药代动力学分析，将奥沙利铂的给药时间移至第2天。卡培他滨，5'-脱氧-5-氟胞苷，5'-脱氧-5的血浆浓度用高效液相色谱法分析了-氟尿苷（5'-DFUR）和5-FU。CES1多态性（rs3217164，rs2244614，rs2244613，rs7187684，和rs11861118）和功能CES1基因（1A1，var1A1，1A2，和伪1A3通过直接测序分析其双型构型中的）。

结果

从2017年9月至2020年2月，共有37例患者入选。血浆浓度-时间曲线与卡培他滨剂量比（AUC /剂量）下的5'-DFUR比其平均值高的区域显示总体≥级的频率更高3卡培他滨的毒性和相对剂量强度（RDI）比比例较低的卡培他滨低。更高的CES1活性表示为比其平均值低的代谢率（卡培他滨的AUC /每种代谢物的三个AUC的总和）与较高的5'-DFUR AUC /剂量和较低的RDI相关，表明CES1在卡培他滨激活生产中的重要作用5′-DFUR。但是，CES1变体与卡培他滨的药代动力学和毒性之间的关联并不明显。

结论

CES1变体与卡培他滨的药代动力学和毒性无关。