Genetic polymorphisms of CYP2B6 affect the pharmacokinetics/pharmacodynamics of cyclophosphamide in Japanese cancer patients
Genetic polymorphisms of CYP2B6 affect the pharmacokinetics/pharmacodynamics of cyclophosphamide in Japanese cancer patients
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DOI：
10.1097/fpc.0b013e328045c4fb
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发表时间：
2007-06-01
影响因子：
2.6
通讯作者：
Minami, Hironobu
中科院分区：
文献类型：
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作者：
Nakajima, Miki;Komagata, Sayaka;Minami, Hironobu
目的探讨药物代谢酶基因多态性对环磷酰胺及其活性代谢产物4-羟基环磷酰胺的药代动力学及药效学的影响。实验设计103例日本恶性淋巴瘤或乳腺癌患者接受环磷酰胺（500-750 mg/m2）治疗。采用高效液相色谱法测定环磷酰胺和4-羟基环磷酰胺的血药浓度，计算药代动力学参数。采用等位基因特异性聚合酶链反应（PCR）或聚合酶链反应-限制性片段长度多态性（PCR-RFLP）方法检测CYP 2B 6、CYP 2C 19、CYP 3A 4、CYP 3A 5、ALDMA 1、GST基因型。我们首先证明了白细胞减少和中性粒细胞减少是显著的（PC（5 '-侧翼区），g.15582C>T（内含子3），或g.18492T>C（内含子5），具有显著更低的4-羟基环磷酰胺/环磷酰胺的曲线下面积比，表明环磷酰胺4-羟基化降低。特别重要的是发现白细胞减少症与单核苷酸多态性g显著相关。- 2320T > C，g. - 750 T> C和g.18492T>C，两者高度连锁。环磷酰胺或4-羟基环磷酰胺的药代动力学和遗传多态性的其他enzymes.Conclusions我们澄清，在启动子区或内含子的单核苷酸多态性的CYP 2B 6影响环磷酰胺激活的效力，4-羟基环磷酰胺的药代动力学之间没有关系。这些信息对预测环磷酰胺的不良反应和临床疗效有价值。
Objective To evaluate the effects of genetic polymorphisms of drug metabolizing enzymes on the pharmacolkinetics of cyclophosphamide and its active metabolite, 4-hydroxycyclophosphamide, and on the pharmacodynamics.Experimental Design One hundred and three Japanese patients with malignant lymphoma or breast cancer treated with cyclophosphamide (500-750 mg/m(2)) participated in this study. The plasma concentrations of cyclophosphamide and 4-hydroxycyclophosphamide were determined by high-performance liquid chromatography, and pharmacolkinetic parameters were calculated. The genotypes of CYP2B6, CYP2C19, CYP3A4, CYP3A5, ALDMA1, GST genes were determined by allele-specific polymerase chain reaction or polymerase chain reaction-restriction -fragment length polymorphism.Results A large interindividual difference (54-fold) was observed in the area under the curve ratio of 4-hydroxycyclophosphamide/cyclophosphamide calculated as the metabolic index. We first proved that leukocytopenia and neutropenia were significantly (PC (5'-flanking region), g.15582C>T (intron 3), or g.18492T>C (intron 5), had significantly lower area under the curve ratios of 4-hydroxycyclophosphamide/cyclophosphamide, indicating a decreased cyclophosphamide 4-hydroxylation. Of particular importance was the finding that leukocytopenia was significantly related to the single nucleotide polymorphisms g. - 2320T > C, g. - 750T > C, and g.18492T>C in CYP2B6 gene, which are highly linked. No relationship was observed between the pharmacokinetics of cyclophosphamide or 4-hydroxycyclophosphamide and genetic polymorphisms of the other enzymes.Conclusions We clarified that the single nucleotide polymorphisms in the promoter region or introns in the CYP2B6 affect the potency of cyclophosphamide activation to 4-hydroxycyclophosphamide. This information would be valuable for predicting adverse reactions and the clinical efficacy of cyclophosphamide.