Irinotecan-induced diarrhea: Functional significance of the polymorphic ABCC2 transporter protein
Irinotecan-induced diarrhea: Functional significance of the polymorphic ABCC2 transporter protein
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DOI：
10.1038/sj.clpt.6100019
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发表时间：
2007-01-01
影响因子：
6.7
通讯作者：
Sparreboom, A.
中科院分区：
文献类型：
--
作者：
de Jong, F. A.;Scott-Horton, T. J.;Sparreboom, A.
抗癌药伊立替康的个体间药代动力学变异性很高。在接受伊立替康治疗的患者中，高达 25% 的患者观察到危及生命的腹泻，并且与伊立替康药代动力学和 UGT1A1 基因型状态相关。在这里，我们探讨了 ABCC2 (MRP2) 多态性和单倍型与伊立替康处置和腹泻的关联。一组 167 名白人癌症患者先前接受了伊立替康药代动力学（每 21 天输注 90 分钟）、毒性和 UGT1A1*28 基因型的评估，并使用焦磷酸测序对 ABCC2 的多态性进行了基因分型。在所研究的患者中鉴定出 15 个 ABCC2 单倍型。单倍型 ABCC2*2 与较低的伊立替康清除率相关（28.3 vs 31.6 l/h；P = 0.020）。在不携带 UGT1A1*28 等位基因的患者中，ABCC2*2 单倍型患者的严重腹泻显着减少（10% 与 44%；比值比，0.15；95% 置信区间，0.04-0.61；P = 0.005）。在至少具有一个 UGT1A1*28 等位基因的患者中未观察到这种效应（32% 与 20%；比值比，1.87；95% 置信区间，0.49-7.05；P = 0.354）。这项研究表明，ABCC2*2 单倍型的存在与伊立替康相关腹泻较少相关，可能是由于伊立替康肝胆分泌减少所致。由于在没有因 UGT1A1*28 引起腹泻的遗传倾向的患者中发现了这种关联，因此有必要对 ABCC2 基因型与伊立替康处置和毒性之间的关系进行验证性研究。
Interindividual pharmacokinetic variability of the anticancer agent irinotecan is high. Life-threatening diarrhea is observed in up to 25% of patients receiving irinotecan and has been related with irinotecan pharmacokinetics and UGT1A1 genotype status. Here, we explore the association of ABCC2 (MRP2) polymorphisms and haplotypes with irinotecan disposition and diarrhea. A cohort of 167 Caucasian cancer patients who were previously assessed for irinotecan pharmacokinetics (90-min infusion given every 21 days), toxicity, and UGT1A1*28 genotype were genotyped for polymorphisms in ABCC2 using Pyrosequencing. Fifteen ABCC2 haplotypes were identified in the studied patients. The haplotype ABCC2*2 was associated with lower irinotecan clearance (28.3 versus 31.6 l/h; P = 0.020). In patients who did not carry a UGT1A1*28 allele, a significant reduction of severe diarrhea was noted in patients with the ABCC2*2 haplotype (10 versus 44%; odds ratio, 0.15; 95% confidence interval, 0.04-0.61; P = 0.005). This effect was not observed in patients with at least one UGT1A1*28 allele (32 versus 20%; odds ratio, 1.87; 95% confidence interval, 0.49-7.05; P = 0.354). This study suggests that the presence of the ABCC2*2 haplotype is associated with less irinotecan-related diarrhea, maybe as a consequence of reduced hepatobiliary secretion of irinotecan. As the association was seen in patients not genetically predisposed at risk for diarrhea due to UGT1A1*28, confirmatory studies of the relationships of ABCC2 genotypes and irinotecan disposition and toxicity are warranted.