Abstract：
Hand-Foot syndrome (HFS) and diarrhoea are dose-limiting Adverse Drug Reactions (ADRs) of capecitabine-based chemotherapy. Four polymorphisms in the dihydropyrimidine dehydrogenase (DPYD) gene, encoding the DPD enzyme responsible for the metabolism of fluoropyrimidines, such as capecitabine, are strongly associated with severe ADRs, and their screening should be performed before starting treatment. Moreover, capecitabine-related toxicity may worsen due to drug-drug and drug-supplement interactions. Here we investigated factors responsible for severe HFS and diarrhoea presented by two patients, non-carriers of the recommended DPYD single nucleotide polymorphisms (SNPs) but carriers of other genetic variants suggested to increase the risk of capecitabine-related ADRs. Through careful therapy recognition, we demonstrated that, unbeknownst to the oncologists, the patients were taking folic acid during the treatment with capecitabine at a dosage higher than 2000 mg/m2, which is the maximum tolerated dose when folate is administered. To resolve the ADRs, the therapy had to be drastically changed. In one case, dose reduction of capecitabine and discontinuation of lipid-lowering agents were carried out. In the other case, discontinuation of capecitabine and folic acid and capecitabine re-administration were performed after a month. Genetic and environmental factors should be considered good predictors of severe capecitabine-related toxicity. Medication reconciliation should be encouraged to avoid the harmful consequences of inappropriate treatments.
摘要：
手足综合征（HFS）和腹泻是以卡培他滨为基础的化疗的剂量限制性药物不良反应（ADR）。二氢嘧啶脱氢酶（DPYD）基因的四个多态性，编码负责氟嘧啶代谢的DPD酶，如卡培他滨，与严重的不良反应密切相关，他们的筛查应在开始治疗前进行。此外，卡培他滨相关毒性可能由于药物-药物和药物-补充剂的相互作用而恶化。在这里，我们调查了导致两名患者出现严重HFS和腹泻的因素，推荐的DPYD单核苷酸多态性(SNPs)的非携带者和其他遗传变异的携带者提示卡培他滨相关ADR的风险增加.通过仔细的治疗识别，我们证明了，肿瘤学家不知道，患者在接受卡培他滨治疗期间服用的叶酸剂量高于2000mg/m2,这是服用叶酸时的最大耐受剂量.为了解决ADR，治疗必须彻底改变。在一个案例中,减少卡培他滨的剂量并停用降脂药.在另一种情况下，1个月后停用卡培他滨和叶酸,并再次给予卡培他滨.遗传和环境因素应被认为是卡培他滨严重毒性的良好预测因子。应鼓励药物协调，以避免不适当治疗的有害后果。
