Division of Cancer Genome and Pharmacotherapy, Department of Clinical Pharmacy, Showa University School of Pharmacy, 1-5-8 Hatanodai, Shinagawa-ku, Tokyo, 142-8555, Japan.
Division of Medical Oncology, Department of Medicine, Showa University School of Medicine, 1-5-8 Hatanodai, Shinagawa-ku, Tokyo, 142-8555, Japan.
Cancer Chemother Pharmacol. 2020 Jun;85(6):1119-1128. doi: 10.1007/s00280-020-04087-z. Epub 2020 May 26.
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.
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) 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.
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.
CES1 variants are not associated with capecitabine pharmacokinetics and toxicity.
卡培他滨是一种前体药物，在体内经三步代谢形成活性 5-氟尿嘧啶（5-FU）。第一步主要由肝羧酸酯酶（CES）1 催化。在此，我们研究了 CES1 变体对卡培他滨药代动力学和毒性的影响。
我们招募了接受辅助卡培他滨加奥沙利铂（CapeOX）治疗的结直肠癌（CRC）术后患者和接受 CapeOX 治疗的转移性 CRC 患者。在第 1 天进行第 1 次卡培他滨（1000mg/m）剂量的药代动力学分析，并将奥沙利铂给药时间改为第 2 天。采用高效液相色谱法分析卡培他滨、5'-脱氧-5-氟胞苷、5'-脱氧-5-氟尿苷（5'-DFUR）和 5-FU 的血浆浓度。通过直接测序分析 CES1 多态性（rs3217164、rs2244614、rs2244613、rs7187684 和 rs11861118）和功能性 CES1 基因（1A1、var1A1、1A2 和伪 1A3）在其二倍型构型中的情况。
2017 年 9 月至 2020 年 2 月期间共招募了 37 名患者。5'-DFUR 血药浓度-时间曲线下面积与卡培他滨剂量比值（AUC/dose）高于平均值的患者，其总体≥3 级毒性的发生频率更高，卡培他滨相对剂量强度（RDI）更低。CES1 活性表示为代谢比（卡培他滨 AUC 与每个代谢物的三个 AUC 之和的比值）低于平均值与 5'-DFUR AUC/dose 更高和 RDI 更低相关，表明 CES1 在卡培他滨激活生成 5'-DFUR 中起重要作用。然而，CES1 变体与卡培他滨药代动力学和毒性之间的关联并不显著。
CES1 变体与卡培他滨的药代动力学和毒性无关。
