Bosch Tessa M, Huitema Alwin D R, Doodeman Valerie D, Jansen Robert, Witteveen Els, Smit Wim M, Jansen Rob L, van Herpen Carla M, Soesan Marcel, Beijnen Jos H, Schellens Jan H M
Department of Pharmacy and Pharmacology, The Netherlands Cancer Institute/Slotervaart Hospital, Louwesweg 6, 1066 EC Amsterdam, the Netherlands.
Clin Cancer Res. 2006 Oct 1;12(19):5786-93. doi: 10.1158/1078-0432.CCR-05-2649.
Despite the extensive clinical experience with docetaxel, unpredictable interindividual variability in efficacy and toxicity remain important limitations associated with the use of this anticancer drug. Large interindividual pharmacokinetic variability has been associated with variation in toxicity profiles. Genetic polymorphisms in drug-metabolizing enzymes and drug transporters could possibly explain the observed pharmacokinetic variability. The aim of this study was therefore to investigate the influence of polymorphisms in the CYP3A and ABCB1 genes on the population pharmacokinetics of docetaxel.
Whole blood samples were obtained from patients with solid tumors and treated with docetaxel to quantify the exposure to docetaxel. DNA was collected to determine polymorphisms in the CYP3A and ABCB1 genes with DNA sequencing. A population pharmacokinetic analysis of docetaxel was done using nonlinear mixed-effect modeling.
In total, 92 patients were assessable for pharmacokinetic analysis of docetaxel. A three-compartmental model adequately described the pharmacokinetics of docetaxel. Several polymorphisms in the CYP3A and ABCB1 genes were found, with allele frequencies of 0.54% to 48.4%. The homozygous C1236T polymorphism in the ABCB1 gene (ABCB1*8) was significantly correlated with a decreased docetaxel clearance (-25%; P = 0.0039). No other relationships between polymorphisms and pharmacokinetic variables reached statistical significance. Furthermore, no relationship between haplotypes of CYP3A and ABCB1 and the pharmacokinetics could be identified.
The polymorphism C1236T in the ABCB1 gene was significantly related to docetaxel clearance. Our current finding may provide a meaningful tool to explain interindividual differences in docetaxel treatment in daily practice.
尽管多西他赛已有广泛的临床应用经验，但疗效和毒性方面不可预测的个体间差异仍是使用这种抗癌药物的重要局限。较大的个体间药代动力学差异与毒性特征的变化有关。药物代谢酶和药物转运体的基因多态性可能解释所观察到的药代动力学差异。因此，本研究的目的是调查CYP3A和ABCB1基因多态性对多西他赛群体药代动力学的影响。
从实体瘤患者中获取全血样本，用多西他赛进行治疗以量化多西他赛的暴露量。收集DNA以通过DNA测序确定CYP3A和ABCB1基因的多态性。使用非线性混合效应模型对多西他赛进行群体药代动力学分析。
总共92例患者可用于多西他赛的药代动力学分析。三室模型能充分描述多西他赛的药代动力学。在CYP3A和ABCB1基因中发现了几种多态性，等位基因频率为0.54%至48.4%。ABCB1基因中的纯合C1236T多态性（ABCB1*8）与多西他赛清除率降低显著相关（-25%；P = 0.0039）。多态性与药代动力学变量之间的其他关系均未达到统计学意义。此外，未发现CYP3A和ABCB1的单倍型与药代动力学之间存在关系。
ABCB1基因中的C1236T多态性与多西他赛清除率显著相关。我们目前的发现可能为解释日常实践中多西他赛治疗的个体差异提供一个有意义的工具。
