Tran A, Jullien V, Alexandre J, Rey E, Rabillon F, Girre V, Dieras V, Pons G, Goldwasser F, Tréluyer J M
Ecole Pratique des Hautes Etudes, Pharmacologie, Faculté de Médecine, Groupe Hospitalier Cochin St Vincent de Paul, AP-HP, Université Paris-Descartes, Paris, France.
Clin Pharmacol Ther. 2006 Jun;79(6):570-80. doi: 10.1016/j.clpt.2006.02.003. Epub 2006 May 2.
Patients initiating docetaxel chemotherapy were genotyped for CYP3A4, CYP3A5, MDR1, GSTM1, GSTT1, GSTM3, and GSTP1 to identify variability factors of docetaxel pharmacokinetics and toxicity.
Genotyping was performed by direct sequencing (CYP3A4), real-time polymerase chain reaction (CYP3A5), and polymerase chain reaction-restriction fragment length polymorphism (MDR1 and GST). The clearance and area under the curve of docetaxel were calculated by use of a Bayesian approach. Absolute neutrophil count was recorded twice weekly.
With regard to the pharmacokinetic analysis, 58 patients were included. CYP3A4*1B carriers (*1A/1B, n=4), who are also CYP3A51/*3 carriers, had a significantly higher clearance and lower dose-normalized area under the curve of docetaxel than those with the wild genotype (*1A/1A, n=53): 55.2+/-13.5 L/h versus 37.3+/-11.7 L/h (P=.01) and 31.4+/-6.2 (microg . h/L)/(mg/m(2)) versus 52.7+/-18.2 (microg . h/L)/(mg/m(2)) (P=.005), respectively. No influence of MDR1 was evidenced. With regard to the pharmacodynamic analysis, febrile neutropenia occurred more frequently in GSTP1A/*B carriers (31.6% versus 3.7% in *A/*A carriers and 0% in *A/*C, *B/*B, and *B/*C carriers) (P=.037). Grade 3 neutropenia occurred more frequently in 3435TT MDR1 genotype carriers: TT, 100%; CT, 77.3%; and CC, 54.5% (P=.046). No influence of GSTM1, GSTT1, or GSTM3 polymorphisms was evidenced on docetaxel toxicity.
Patients carrying the CYP3A1B allele may have enhanced docetaxel clearance and may be underexposed, whereas those carrying GSTP1A/*B and 3435TT genotypes may have excessive hematologic toxicity. Further studies are warranted to determine the usefulness of genotyping before docetaxel treatment.
对开始多西他赛化疗的患者进行CYP3A4、CYP3A5、MDR1、GSTM1、GSTT1、GSTM3和GSTP1基因分型，以确定多西他赛药代动力学和毒性的变异因素。
采用直接测序法（CYP3A4）、实时聚合酶链反应（CYP3A5）以及聚合酶链反应-限制性片段长度多态性分析（MDR1和谷胱甘肽S-转移酶）进行基因分型。使用贝叶斯方法计算多西他赛的清除率和曲线下面积。每周记录两次绝对中性粒细胞计数。
在药代动力学分析方面，纳入了58例患者。CYP3A4*1B携带者（*1A/1B，n = 4），同时也是CYP3A51/*3携带者，其多西他赛的清除率显著更高，剂量标准化曲线下面积显著更低，与野生型（*1A/1A，n = 53）相比：分别为55.2±13.5 L/h对37.3±11.7 L/h（P = 0.01）以及31.4±6.2（μg·h/L）/（mg/m²）对52.7±18.2（μg·h/L）/（mg/m²）（P = 0.005）。未证明MDR1有影响。在药效学分析方面，GSTP1A/*B携带者发热性中性粒细胞减少症发生频率更高（*A/*A携带者为3.7%，*A/*C、*B/B和B/*C携带者为0%，*A/*B携带者为31.6%）（P = 0.037）。3435TT MDR1基因型携带者3级中性粒细胞减少症发生频率更高：TT为100%；CT为77.3%；CC为54.5%（P = 0.046）。未证明GSTM1、GSTT1或GSTM3基因多态性对多西他赛毒性有影响。
携带CYP3A1B等位基因的患者可能多西他赛清除率增强且可能暴露不足，而携带GSTP1A/*B和3435TT基因型的患者可能有过度的血液学毒性。有必要进一步研究以确定多西他赛治疗前基因分型的实用性。
