Nakajima Miki, Fujiki Yuto, Kyo Satoru, Kanaya Taro, Nakamura Mitsuhiro, Maida Yoshiko, Tanaka Masaaki, Inoue Masaki, Yokoi Tsuyoshi
Drug Metabolism and Toxicology, Division of Pharmaceutical Sciences, Graduate School of Medical Science, Kanazawa University, Kakuma-machi, Kanazawa 920-1192, Japan.
J Clin Pharmacol. 2005 Jun;45(6):674-82. doi: 10.1177/0091270005276204.
Interindividual differences in the pharmacokinetics of paclitaxel and its metabolites in Japanese ovarian cancer patients were investigated in relation to genetic polymorphisms of the CYP2C8, CYP3A4, and MDR1 genes. The area under the concentration-time curve (AUC) ratios of paclitaxel/6alpha-hydroxypaclitaxel and paclitaxel/3 -p-hydroxypaclitaxel calculated as the metabolic index of CYP2C8 and CYP3A4 showed 13- and 12-fold interindividual variations, respectively. No patient had any CYP2C8 variants, while 2 patients were heterozygotes of CYP3A4*16. For the MDR1 gene, the frequencies of -129C, 1236C, 2677T, 2677A, and 3435T alleles were 2.2%, 8.7%, 56.5%, 4.4%, and 52.2%, respectively. Subjects possessing the 3435T allele had a significantly (P < .05) higher AUC of 3'- p-hydroxypaclitaxel compared to those possessing the 3435C allele. Leukocytopenia was significantly (P < .05) related to the AUC of paclitaxel. Genotyping of the CYP2C8, CYP3A4, and MDR1 genes might not be essential to predict adverse effects of paclitaxel in Japanese patients, although an allelic variant of MDR1 may functionally affect the pharmacokinetics of its metabolite.
在日本卵巢癌患者中，研究了紫杉醇及其代谢产物药代动力学的个体间差异与CYP2C8、CYP3A4和MDR1基因多态性的关系。作为CYP2C8和CYP3A4代谢指标计算的紫杉醇/6α-羟基紫杉醇和紫杉醇/3 -对羟基紫杉醇的浓度-时间曲线下面积（AUC）比值分别显示出13倍和12倍的个体间差异。没有患者有任何CYP2C8变异，而有2名患者是CYP3A4*16的杂合子。对于MDR1基因，-129C、1236C、2677T、2677A和3435T等位基因的频率分别为2.2%、8.7%、56.5%、4.4%和52.2%。与携带3435C等位基因的受试者相比，携带3435T等位基因的受试者3'-对羟基紫杉醇的AUC显著更高（P <.05）。白细胞减少与紫杉醇的AUC显著相关（P <.05）。对日本患者而言，CYP2C8、CYP3A4和MDR1基因的基因分型可能对预测紫杉醇的不良反应并非至关重要，尽管MDR1的一个等位基因变异可能在功能上影响其代谢产物的药代动力学。
