SLCO1B1c.521T＞C基因多态性与大剂量甲氨蝶呤治疗儿童急性淋巴细胞白血病药代动力学及疗效评价  

SLCO1B1c.521T 〉 C gene polymorphisms are associated with high-dose methotrexate pharmacokinetics and clinical outcome of pediatric acute lymphoblastic leukemia

作　　者：张华年[1] 何学连[2] 李建新[3] 汪洋[1] 王诚[4] 陈渝军[1] 牛长河[1] 高萍[1] 

机构地区：[1]武汉市儿童医院临床药理室,430016 [2]武汉市儿童医院临床研究中心,430016 [3]武汉市儿童医院血液内科,430016 [4]苏州大学附属儿童医院临床药学室

出　　处：《中华儿科杂志》2014年第10期770-776,共7页Chinese Journal of Pediatrics

基　　金：湖北省卫生厅2011-2012年科研项目（JX5B74）

摘　　要：目的 探讨SLCO1B1c.521 T＞C基因变异对大剂量甲氨蝶呤治疗儿童急性淋巴细胞白血病（ALL）药代动力学和临床疗效的影响.方法 选择2008年1月至2013年12月武汉市儿童医院血液内科收治的82例ALL患儿为研究对象,依据基因分型结果,将患儿分为SLCO1B1c.521T＞C基因变异组和未变异组.参考ALL-BFM 2000化疗方案,甲氨蝶呤化疗剂量为3～5 g/m2静脉滴注给药;四氢叶酸于甲氨蝶呤用药36 h后开始解救,并根据第48小时甲氨蝶呤血药浓度进行调整.固相萃取高效液相色谱法（Spe-HPLC）分析24、48、72 h血清中甲氨蝶呤及其代谢产物7-OH甲氨蝶呤浓度.NLME群体药代动力学方法估算药代动力学参数;比较两组患儿药代动力学、毒性反应、四氢叶酸解救剂量,随访5年ALL复发率及无事件生存率.结果 82例ALL患儿中SLCO1B1c.521T＞C变异组21例[突变杂合子型（TC） 20例,突变纯合子型（CC）1例],未变异组[野生纯合子型（TT）]61例.SLCO1B1c.521T＞C变异组患儿48、72 h甲氨蝶呤血药浓度明显高于未变异组,差异有统计学意义[48 h：（1.00±1.41）比（0.34±0.17） μmol/L,t=2.131,P=0.046;72 h：（0.31 ±0.26）比（0.08±0.04）μmol/L;t=3.995,P=0.001].变异组48 h后甲氨蝶呤血药浓度曲线下面积（AUC48-∞）为（23.18±19.91）h·μmol/L,明显高于未变异组（t=4.025,P=0.001）.变异组患儿超甲氨蝶呤血药浓度安全阈值（0.1 μmol/L）时间（TC＞01μmol/L）显著高于未变异组,差异有统计学意义[（95.3±22.0）比（67.1±7.5）h,t=5.880,P＜0.001];变异组患儿所需四氢叶酸解救平均剂量高于未变异组,差异有统计学意义[（312.7 ±287.8）比（140.6±27.5） mg/m2;=2.614,P=0.017].变异组患儿胃肠道和肝脏严重毒性反应（Ⅲ～Ⅳ级）的发生率均显著高于未变异组[胃肠道33％（7/21）比5％ （3/61）;肝脏：24％（5/21）比2％（1/61）],差异均有统计学意义（x 2=9.275、8.289,P均＜0.05）.变异�Objective To provide guidance for the high-dose methotrexate （HD-MTX） treatment of pediatric acute lymphoblastic leukemia （ALL）,and to understand the impact of SLCO1B1c.521T 〉 C （rs4149056） variant on methotrexate （MTX） pharmacokinetics and clinical outcome in children with ALL.Method Eighty-two children with ALL in Division of Hematology of Wuhan Children＇s Hospital from January 2008 to February 2013 were enrolled.All patients were genotyped for rs4149056 single nucleotide polymorphism （SNP） into wild-type group （TT genotype） and variant group （TC/CC genotype）.According to the ALL-BFM 2000 protocol,all patients received intravenous infusion of MTX everv ten days at 3 to 5 g/m2.Leucovorin rescue was performed after 36 hours of the MTX administration and its dose was adjusted according to the MTX plasma concentration at 48 hours.The concentrations of MTX and its metabolite at 24,48 and 72 h were determined by high performance liquid chromatography with solid phase extraction.Population pharmacokinetic parameters were estimated by the NLME software.The pharmacokinetics,toxicity and leucovorin rescue was compared.The relapse rate within 5 years and event-free survival were followed up.Result Eighty-two pediatric patients were classified into two groups：variant group including 20 TC genotype carriers and one CC genotype carrier,wild-type group included 61 patients with TT genotype.Compared with wild-type group,plasma concentration of MTX at 48 and 72 h increased significantly [48 h：（1.00±1.41） vs.（0.34±0.17） μmol/L,t =2.131,P=0.046;72 h：（0.31 ± 0.26） vs.（0.08 ± 0.04） μmol/L; t =3.995,P =0.001].Area under the concentration time curve （AUC48-∞） of MTX significantly increased in variant group [（23.18± 19.91） vs.（5.66± 2.01） h · μmoL/L] （t =4.025,P =0.001）.Time above the MTX safety threshold （TC〉0.1 μmol/L） increased significantly in variant group [（95.3 ±22.0） vs.（67.1 ±7.5） h,t =5.880,P 〈0.001].Rescue dosage of leucovor

关 键 词：甲氨蝶呤 突变 药代动力学 

分 类 号：R733.71[医药卫生—肿瘤]