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：
10.1136/ijgc-00009577-200605000-00004
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发表时间：
2005-12
期刊：
影响因子：
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通讯作者：
Hiroaki Yamaguchi;T. Hishinuma;Naomi Endo;Hiroki Tsukamoto;Yukinaga Kishikawa;Mitsumoto Sato;Yuriko Murai;Masahiro Hiratsuka;K. Ito;C. Okamura;Nobuo Yaegashi;N. Suzuki;Yoshihisa Tomioka;Junichi Goto
中科院分区：
文献类型：
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作者：
Hiroaki Yamaguchi;T. Hishinuma;Naomi Endo;Hiroki Tsukamoto;Yukinaga Kishikawa;Mitsumoto Sato;Yuriko Murai;Masahiro Hiratsuka;K. Ito;C. Okamura;Nobuo Yaegashi;N. Suzuki;Yoshihisa Tomioka;Junichi Goto
紫杉醇是一种用于治疗卵巢癌的抗肿瘤药物，由细胞色素P450（CYP）3A4和CYP2C8代谢，并通过ATP结合盒（ABCB1）（多药耐药[MDR1]，P - 糖蛋白）从细胞排出。这些蛋白质的表达受孕烷X受体（PXR）调节。尽管在编码这些蛋白质的基因中存在常见的基因多态性，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例卵巢癌患者中紫杉醇的药代动力学与CYP2C8、CYP3A5、ABCB1和PXR基因多态性的关系。我们发现两种代谢产物6α - 羟基紫杉醇和p - 3′ - 羟基紫杉醇的血浆浓度个体间差异较大。所有患者的CYP2C8基因型均为*1/*1。CYP3A5 A6986G（CYP3A5*3）和PXR C - 25385T等位基因均与紫杉醇及其代谢产物的血浆浓度改变无关。然而，ABCB1 T - 129C、T1236C和G2677（A，T）与紫杉醇的血浆浓度 - 时间曲线下面积（AUC）降低有关。我们还观察到每个患者的AUC（r = - 0.721）或紫杉醇的总清除率（CLtot）（r = 0.673）与ABCB1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，ABCB1基因分型可预测紫杉醇药代动力学的个体间差异。
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, 6α-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.