Genetic variation in ABCB1 influences paclitaxel pharmacokinetics in Japanese patients with ovarian cancer
Genetic variation in ABCB1 influences paclitaxel pharmacokinetics in Japanese patients with ovarian cancer
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DOI：
10.1111/j.1525-1438.2006.00593.x
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发表时间：
2006-05-01
影响因子：
4.8
通讯作者：
Goto, J.
中科院分区：
文献类型：
--
作者：
Yamaguchi, H.;Hishinuma, T.;Goto, J.
紫杉醇是一种用于治疗卵巢癌的抗肿瘤药物，经细胞色素P450（CYP）3A 4和CYP 2C 8代谢，并通过ATP结合盒（ABCB 1）（多药耐药[MDR 1]，P-糖蛋白）从细胞中排出。这些蛋白质的表达受PXR（英语：PXR receptor）调节。虽然编码这些蛋白质的基因存在共同的遗传多态性，但它们对紫杉醇临床疗效的影响尚不清楚。因此，我们研究了13例卵巢癌患者的紫杉醇药代动力学与CYP 2C 8、CYP 3A 5、ABCB 1和PXR多态性的关系。我们发现两种代谢产物6 α-羟基紫杉醇和p-3 '-羟基紫杉醇的血浆浓度存在高度个体间变异性。所有患者的基因型均为CYP 2C 8 *1/*1。CYP 3A 5 A6986 G（CYP 3A 5 *3）和PXR C-25385 T等位基因均与紫杉醇及其代谢物的血浆浓度变化无关。然而，ABCB 1 T-129 C、T1236 C和G2677（A，T）与紫杉醇的血浆浓度-时间曲线下面积（AUC）较低相关。我们还观察到AUC（r=-0.721）或紫杉醇总清除率（CLtot）（r= 0.673）与每例患者的ABCB 1突变等位基因剂量之间存在显著相关性。综上所述，我们的研究结果表明，紫杉醇药代动力学的个体间变异性可以通过ABCB 1基因分型来预测。
Paclitaxel, an antineoplastic agent used for the treatment of ovarian cancer, is metabolized by cytochrome P450 (CYP)3A4 and CYP2C8 and is excreted from cells by ATP-binding cassette (ABCB1) (multi-drug resistance [MDR1], P-glycoprotein). Expression of these proteins is regulated by pregnane X receptor (PXR). Although there are common genetic polymorphisms in the genes encoding these proteins, their effect on the clinical efficacy of paclitaxel is unclear. We therefore examined the relationship of the paclitaxel pharmacokinetics in 13 patients with ovarian cancer to polymorphisms in CYP2C8, CYP3A5, ABCB1, and PXR. We found high interindividual variability in the plasma concentrations of two metabolites, 6 alpha-hydroxypaclitaxel and p-3'-hydroxypaclitaxel. All the patients were genotyped as CYP2C8*1/*1. Neither the CYP3A5 A6986G (CYP3A5*3) nor the PXR C-25385T alleles were associated with altered plasma concentrations of paclitaxel and its metabolites. ABCB1 T-129C, T1236C, and G2677(A,T), however, was associated with lower area under the plasma concentration-time curve (AUC) of paclitaxel. We also observed a significant correlation between the AUC (r=-0.721) or the total clearance of paclitaxel (CLtot) (r= 0.673) and the ABCB1 mutant allele dosage in each patient. Taken together, our findings suggest that interindividual variability in paclitaxel pharmacokinetics could be predicted by ABCB1 genotyping.