Yamaguchi H, Hishinuma T, Endo N, Tsukamoto H, Kishikawa Y, Sato M, Murai Y, Hiratsuka M, Ito K, Okamura C, Yaegashi N, Suzuki N, Tomioka Y, Goto J
Division of Clinical Pharmacy, Graduate School of Pharmaceutical Sciences, Tohoku University Hospital, 1-1 Seiryo-machi, Aoba-ku, Sendai 980-8574, Japan.
Int J Gynecol Cancer. 2006 May-Jun;16(3):979-85. doi: 10.1111/j.1525-1438.2006.00593.x.
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, 6alpha-hydroxypaclitaxel and p-3'-hydroxypaclitaxel. All the patients were genotyped as CYP2C8*1/1. Neither the CYP3A5 A6986G (CYP3A53) 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 (CL(tot)) (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.
紫杉醇是一种用于治疗卵巢癌的抗肿瘤药物，通过细胞色素P450（CYP）3A4和CYP2C8代谢，并通过ATP结合盒转运体（ABCB1）（多药耐药蛋白[MDR1]，P-糖蛋白）从细胞中排出。这些蛋白的表达受孕烷X受体（PXR）调控。尽管编码这些蛋白的基因存在常见的基因多态性，但其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基因多态性之间的关系。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存在高度个体间差异。所有患者的基因型均为CYP2C8*1/1。CYP3A5 A6986G（CYP3A53）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）与紫杉醇血浆浓度-时间曲线下面积（AUC）降低有关。我们还观察到每位患者的AUC（r = -0.721）或紫杉醇的总清除率（CL(tot)）（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。
