State Key Laboratory for Diagnosis and Treatment of Infectious Disease, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, Zhejiang Provincial Key Laboratory for Drug Clinical Research and Evaluation, The First Affiliated Hospital , Zhejiang University , 79 QingChun Road , Hangzhou , Zhejiang 310000 , People's Republic of China.
Zhejiang Institute for Food and Drug Control , Hangzhou , Zhejiang 310004 , People's Republic of China.
Chem Res Toxicol. 2018 Oct 15;31(10):1069-1079. doi: 10.1021/acs.chemrestox.8b00150. Epub 2018 Oct 1.
Hand-foot syndrome (HFS), the most common side effect of capecitabine, is a dose-limiting cutaneous toxicity with only rare therapeutic options. The causative mechanisms of HFS are still unclear. Many studies suggested that capecitabine or its metabolites caused the toxicity. This study is attempting to determine if there are any new metabolites that may be present and be linked to toxicity. For this purpose, 25 patients who ingested capecitabine orally were enrolled and divided into HFS positive and negative groups. Urine and plasma samples were collected before administration and five cycles after administration. Eleven phase I and phase II metabolites of capecitabine were detected and identified by ultraperformance liquid chromatography coupled with quadrupole time-of-flight tandem mass spectrometry with a metabolomic approach and MetaboLynx. Nine novel metabolites of capecitabine were identified herein, which were not observed in the HFS negative group. Their structures were confirmed by chemical synthesis and nuclear magnetic resonance spectroscopy. The cytotoxities of capecitabine and its metabolites on HaCaT cells were measured. Among them, M9/10 exhibited significant inhibitory activity, and they were produced via acetylation mainly by N-acetyltransferase 2. Our study comprehensively described the metabolism of capecitabine in patients with HFS and detected the novel pathways of capecitabine, which was a positive significance for the mechanism of HFS.
手足综合征（HFS）是卡培他滨最常见的副作用，是一种剂量限制的皮肤毒性，只有很少的治疗选择。HFS 的发病机制尚不清楚。许多研究表明，卡培他滨或其代谢物引起了毒性。本研究试图确定是否存在任何可能存在并与毒性相关的新代谢物。为此，本研究纳入了 25 名口服卡培他滨的患者，并将其分为 HFS 阳性和阴性组。在给药前和给药后五个周期收集尿液和血浆样本。采用超高效液相色谱-四极杆飞行时间串联质谱联用代谢组学方法和 MetaboLynx 检测并鉴定了卡培他滨的 11 种 I 期和 II 期代谢物。本研究在此共鉴定了 9 种卡培他滨的新代谢物，这些代谢物在 HFS 阴性组中未观察到。通过化学合成和核磁共振波谱对其结构进行了确认。测定了卡培他滨及其代谢物对 HaCaT 细胞的细胞毒性。其中，M9/10 表现出显著的抑制活性，主要通过 N-乙酰基转移酶 2 产生乙酰化。本研究全面描述了 HFS 患者中卡培他滨的代谢情况，并检测到了卡培他滨的新代谢途径，这对 HFS 的发病机制具有重要意义。
