咪达唑仑作为探针药物对急性白血病患儿细胞色素P450ⅢA酶活性的研究

Enzyme activity of cytochrome P450ⅢA of acute leukemia in children with midazolam as a probe drug

目的探讨细胞色素P450ⅢA酶活性在急性白血病患儿中的个体间差异、影响因素以及活性的高低对化疗后产生肝功能损害的影响。方法对20例急性白血病患儿,5 min内静脉推注0.1 mg/kg咪达唑仑,并在开始推注后15、30、60、120、240和360 min时在对侧静脉抽取静脉血2 mL,分离血浆。应用高效液相色谱法检测咪达唑仑的血浆浓度,采用房室模型分析咪达唑仑的药代动力学参数,计算咪达唑仑的代谢清除率和曲线下面积,作为评估急性白血病患儿细胞色素P450ⅢA酶活性的指标。结果咪达唑仑代谢清除率女性([0.11±0.035)L.h-1.kg-1]高于男性([0.073±0.025)L.h-1.kg-1,=0.014]。急性非淋巴细胞白血病患儿的咪达唑仑代谢清除率[(0.085±0.024)L.h-1.kg-1]略低于急性淋巴细胞白血病患儿[(0.094±0.039)L.h-1.kg-1],但差距无显著性意义(=0.641)。9例高危急性淋巴细胞白血病患儿经过相同的化疗方案,化疗后发生肝功能损害的患儿,其化疗前咪达唑仑代谢清除率[(0.112±0.029)L.h-1.kg-1]低于未发生肝功能损害患儿化疗前[(0.208±0.07)L.h-1.kg-1,=0.026]。结论在急性白血病患儿中应用咪达唑仑作为细胞色素P450ⅢA酶活性探针是安全可行的。急性白血病患儿细胞色素P450ⅢA酶活性存在性别差异;急性白血病患儿细胞色素P450ⅢA酶活性能较好的反映其肝脏代谢化疗药物的能力。

Objective To investigate application of midazolam as in-vivo probe of cytochrome P450ⅢA enzyme ac-tivity（CYP3A activity）,interindividual variations and influential factors of hepatic CYP3A activity in acute leukemia of children.Methods Twenty acute leukemia of children receiving a short i.v.bolus midazolam（dose,0.1 mg/kg）,blood samples were drawn at 15,30,60,120,240 and 360 minutes following administration of midazolam,and blood samples were collected in glass tubes containing heparin.Midazolam concentrations in plasma were determined using liquid chromatography-mass spectrometry,and pharmacokinetic variables were calculated using compartmental analy-sis,and then it＇s clearance and area under the curve were calculated,which were as parameters of CYP3A activity.Re-sults CYP3A activity varies as much as 7-fold in liver of acute leukemia of children.Girls＇ clearance of midazolam（0.11±0.035 L.h^-1.kg^-1） were higher than boys＇（0.073±0.025 L.h^-1.kg^-1）（=0.014）.Clearance of midazolam of acute non-lymphocytic leukemia of children（0.085±0.024 L.h^-1.kg^-1） were lower than that in acute lymphocytic leukemia of children（0.094±0.039 L.h^-1.kg^-1）,but these were not statistically significant（=0.641）.Clearance of midazolam in children of liver functional lesion after chemotherapy were obviously lower than those of non-liver func-tional lesion（0.112±0.029 0.208±0.07 L.h^-1.kg^-1,=0.026） in nine high risk acute lymphoblastic leukemia of children receiving the same chemotherapy.Conclusion As an in-vivo probe of hepatic CYP3A activity,midazolam is secure and feasible in acute leukemia of children.Interindividual variation were obvious in hepatic CYP3A activity of acute leukemia of children,and girls＇ were higher than boys＇.Clearance of midazolam can be used to assess liver function in patients of acute leukemia.