Pharmacogenetics and irinotecan therapy
Pharmacogenetics and irinotecan therapy
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DOI：
10.2146/ajhp060155
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发表时间：
2006-11-15
影响因子：
2.7
通讯作者：
Kolesar, Jill M.
中科院分区：
文献类型：
--
作者：
Kahn, Kristine K.;Wolff, James J.;Kolesar, Jill M.
目的。综述了伊立替康代谢、伊立替康药物遗传学研究以及给药前基因检测的作用。伊立替康在全球范围内被批准用于治疗转移性结直肠癌，但会导致剂量限制性中性粒细胞减少症和腹泻。严重时，这些可导致脱水、感染、患者不适、额外的药物需求、住院和死亡。伊立替康治疗的预测标志物的鉴定一直是药物遗传学研究的一个重要目标。伊立替康的标签最近进行了更改，现在包括警告药物代谢酶尿苷二磷酸葡萄糖醛酸转移酶1A1 （UGT1A1）活性降低的患者有更大的中性粒细胞减少风险。已知的UGT1A1活性降低的标记是遗传变异UGT1A1*28。大量研究表明遗传因素的影响，尤其是UGT1A1*28，导致伊立替康药代动力学和毒性的患者间差异。伊立替康的新标签建议临床医生考虑减少UGT1A1纯合子患者的伊立替康剂量*28。至少部分伊立替康毒性的患者间差异可以用UGT1A1*28多态性来解释。UGT1A1*28等位基因纯合子的患者在接受伊立替康治疗时发生严重中性粒细胞减少的风险增加，特别是300-350 mg/m(2)的治疗方案。现在有一种分子测定方法可用于确定高危亚组，并应由卫生保健专业人员使用，以帮助指导伊立替康治疗决策。
Purpose. Irinotecan metabolism, irinotecan pharmacogenetic research, and the role of genetic testing before administration of the drug are reviewed.Summary. Irinotecan is approved worldwide for the treatment of metastatic colorectal cancer but causes dose-limiting neutropenia and diarrhea. When severe, these can lead to dehydration, infection, patient discomfort, additional medication requirements, hospitalization, and death. The identification of predictive markers in irinotecan therapy has been a significant goal of pharmacogenetic research. The labeling of irinotecan was recently changed and now includes a warning of greater neutropenia risk in patients with reduced activity in the drug-metabolizing enzyme uridine diphosphate glucuronosyltransferase 1A1 (UGT1A1). A known marker of reduced UGT1A1 activity is the genetic variant UGT1A1*28. Numerous studies have demonstrated the effects of genetic factors, especially UGT1A1*28, that contribute to interpatient variability in irinotecan pharmacokinetics and toxicity. Irinotecan's new labeling recommends that clinicians consider reducing the dosage of irinotecan in patients homozygous for UGT1A1*28.Conclusion. At least part of the interpatient variability of irinotecan toxicity can be explained by the UGT1A1*28 polymorphism. Patients who are homozygous for the UGT1A1*28 allele have an increased risk of developing severe neutropenia when receiving irinotecan, especially the 300-350-mg/m(2) regimen. A molecular assay is now available to identify the at-risk subgroup and should be used by health care professionals to help guide irinotecan-treatment decisions.