Pharmacokinetic and pharmacogenetic determinants of the activity and toxicity of irinotecan in metastatic colorectal cancer patients.
Pharmacokinetic and pharmacogenetic determinants of the activity and toxicity of irinotecan in metastatic colorectal cancer patients.
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DOI：
10.1038/sj.bjc.6604673
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发表时间：
2008-10-21
影响因子：
8.8
通讯作者：
Gamelin, E.
中科院分区：
文献类型：
--
作者：
Rouits, E.;Charasson, V.;Petain, A.;Boisdron-Celle, M.;Delord, J-P;Fonck, M.;Laurand, A.;Poirier, A-L;Morel, A.;Chatelut, E.;Robert, J.;Gamelin, E.
本研究旨在建立伊立替康及其代谢物药代动力学变异的遗传和非遗传因素之间的关系，以及伊立替康的药代动力学或代谢参数与其疗效和毒性之间的关系。我们用5-氟尿嘧啶和伊立替康联合治疗了49例转移性结直肠癌患者，研究了UGT1A1基因(TATA框中的TA重复)和CES2基因启动子(830C>；G)的多态性分别作为SN-38葡萄糖醛酸化和伊立替康激活的潜在标志，并通过皮质醇生物转化为6β-羟基皮质醇来评估细胞色素P3A4的潜在活性。没有任何药代动力学参数能直接预测临床结果或毒性。伊立替康的3种重要代谢物SN-38、SN-38葡萄糖醛酸苷和APC的AUC与患者治疗前与药物代谢有关的生物学参数(血肌酐、胆红素、肝酶和血白细胞)初步相关。SN-38AUC与血白细胞数显著相关，SN-38G AUC与血肌酐显著相关，APC AUC与血浆肝酶显著相关。伊立替康的相对激活程度与SN-38葡萄糖醛酸化反应呈负相关。UGT1A1的TATA盒基因多态性与血浆胆红素水平显著相关，是中性粒细胞减少的重要预测因子。皮质醇6β羟化水平可预测腹泻的发生。所有这些观察结果可能会改善伊立替康在结直肠癌患者中的常规使用。UGT1A1基因分型和皮质醇6β羟化测定有助于确定伊立替康的最佳剂量。
This study aims at establishing relationships between genetic and non-genetic factors of variation of the pharmacokinetics of irinotecan and its metabolites; and also at establishing relationships between the pharmacokinetic or metabolic parameters and the efficacy and toxicity of irinotecan. We included 49 patients treated for metastatic colorectal cancer with a combination of 5-fluorouracil and irinotecan; a polymorphism in the UGT1A1 gene (TA repeat in the TATA box) and one in the CES2 gene promoter (830C>G) were studied as potential markers for SN-38 glucuronidation and irinotecan activation, respectively; and the potential activity of CYP3A4 was estimated from cortisol biotransformation into 6β-hydroxycortisol. No pharmacokinetic parameter was directly predictive of clinical outcome or toxicity. The AUCs of three important metabolites of irinotecan, SN-38, SN-38 glucuronide and APC, were tentatively correlated with patients' pretreatment biological parameters related to drug metabolism (plasma creatinine, bilirubin and liver enzymes, and blood leukocytes). SN-38 AUC was significantly correlated with blood leukocytes number and SN-38G AUC was significantly correlated with plasma creatinine, whereas APC AUC was significantly correlated with plasma liver enzymes. The relative extent of irinotecan activation was inversely correlated with SN-38 glucuronidation. The TATA box polymorphism of UGT1A1 was significantly associated with plasma bilirubin levels and behaved as a significant predictor for neutropoenia. The level of cortisol 6β-hydroxylation predicted for the occurrence of diarrhoea. All these observations may improve the routine use of irinotecan in colorectal cancer patients. UGT1A1 genotyping plus cortisol 6β-hydroxylation determination could help to determine the optimal dose of irinotecan.
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