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首页> 外文期刊>Adverse drug reactions and toxicological reviews >The effect of dihydropyrimidine dehydrogenase deficiency on outcomes with fluorouracil.
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The effect of dihydropyrimidine dehydrogenase deficiency on outcomes with fluorouracil.

机译：二氢嘧啶脱氢酶缺乏症对氟尿嘧啶结局的影响。

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The use of fluorouracil has been complicated by unpredictable pharmacokinetics, low response rates and seemingly random toxicity. The variable pharmacology is largely due to inherited differences in expression of the metabolising enzyme dihydropyrimidine dehydrogenase (DPD). This converts fluorouracil to inactive metabolites (catabolic pathway) and ultimately dictates the amount of fluorouracil that is available to be metabolised to cytotoxic nucleotides (anabolic pathway). Absolute and partial DPD deficiency affect around 0.1 and 3% of the Caucasian population, respectively. Administration of conventional doses of fluorouracil to these individuals has resulted in profound bone marrow and gastrointestinal toxicity, especially in those with absolute DPD deficiency. Other forms of toxicity such as myocardial ischaemia have been difficult to attribute directly to DPD deficiency. Efforts to improve outcomes with fluorouracil have included monitoring of fluorouracil concentrations and modifying fluorouraciladministration techniques (e.g. from bolus injections to protracted intravenous infusions). In general, these moves have met with limited therapeutic advancement. The recognition that DPD deficiency increases toxicity has lead to the suggestion that genotypic or phenotypic assessment of DPD status prior to initiating fluorouracil may help predict outcomes. The gene that encodes for DPD expression is called DPYD. Approximately 1% of Caucasians are heterozygotes for the DPYD*2A mutation which is the variant allele that is most frequently implicated in DPD deficiency. Screening for this mutation may identify around 60% of individuals with absolute DPD deficiency who are at the greatest risk of toxicity. Another approach is to determine DPD activity in peripheral blood mononuclear cells, with low activity suggesting an increased risk of toxicity. Intratumoral DPD activity may also be assessed with high activity suggesting a poorer response to fluorouracil. Recently, drugs that inhibit DPD (e.g. eniluracil) have become available. These remove much of the variability in fluorouracil pharmacokinetics and may make assessment of DPD activity redundant. Despite the considerable inroads that have been made, further study is needed before the best means of optimising fluorouracil treatment is determined.
机译：氟尿嘧啶的使用由于不可预测的药代动力学，低响应率和看似随机的毒性而变得复杂。药理学差异的主要原因是代谢酶二氢嘧啶脱氢酶（DPD）表达的遗传差异。这将氟尿嘧啶转化为无活性的代谢产物（分解代谢途径），并最终决定了可被代谢为细胞毒性核苷酸（代谢途径）的氟尿嘧啶的量。 DPD的绝对和部分缺乏分别影响约0.1％和3％的白种人。向这些个体施用常规剂量的氟尿嘧啶已导致严重的骨髓和胃肠道毒性，尤其是在那些绝对DPD缺乏的患者中。其他形式的毒性反应（例如心肌缺血）很难直接归因于DPD缺乏症。改善氟尿嘧啶结果的努力包括监测氟尿嘧啶的浓度和修改氟尿嘧啶的给药技术（例如从推注注射到延长的静脉内输注）。通常，这些措施在治疗上进展有限。 DPD缺乏会增加毒性的认识导致人们提出在开始氟尿嘧啶之前进行DPD状态的基因型或表型评估可能有助于预测结果。编码DPD表达的基因称为DPYD。大约1％的高加索人是DPYD * 2A突变的杂合子，这是最常见与DPD缺乏症有关的变异等位基因。对这种突变的筛查可以确定约60％的绝对DPD缺乏症个体中毒性风险最高。另一种方法是确定外周血单核细胞中的DPD活性，其活性低表明毒性风险增加。肿瘤内DPD活性也可能被评估为高活性，表明对氟尿嘧啶的反应较差。最近，抑制DPD的药物（例如恩尿嘧啶）已经可用。这些消除了氟尿嘧啶药代动力学的大部分可变性，并且可能使DPD活性评估变得多余。尽管取得了相当大的进展，但在确定优化氟尿嘧啶治疗的最佳方法之前，还需要进一步研究。

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