柔红霉素在白血病患儿体内的药代动力学与疗效和毒副反应的相关性研究

目的 研究柔红霉素(DNR)在急性白血病(AL)患儿体内的药代动力学,探讨DNR药代动力学与化疗疗效和毒副反应的相关性.方法 (1)采用高效液相色谱-荧光检测法(HPLC-FR),测定20例AL患儿开始静脉滴注DNR后24 h内不同时点DNR血药浓度,研究其药代动力学.(2)在化疗不同阶段监测骨髓象、外周血白细胞、心电图、超声心动图、心肌酶谱、肝肾功能等指标.结果 (1)DNR在血中以二房室模型衰减,静脉滴注DNR后,血药浓度1～3 h达高峰,峰浓度(Cmax)为63.50 ug/L,平均血浆峰值时间(Tmax)为1.45 h,静脉滴注结束后又迅速降至11.52 ug/L,并维持这一低水平.DNR药代动力学在AL患儿体内个体间差异非常大.清除率(CL)最高值为最低值的9倍,曲线下面积(AUC)为8倍,Cmax为5倍.(2)①CL:男性为57.99 L/(h·m2),女性为93.71L/(h·m2),男性明显低于女性(P<0.05).②Tmax:>6岁组为1.1 h,≤6岁组为1.8 h(P<0.05);Cmax:>6岁组为90.77 ug/L,≤6岁组为57.44 ug/L(P<0.05).结论 (1)DNR在儿童体内的药代动力学个体差异很大,提示治疗效应也可能存在个体差异,需要药物监测.(2)男性及>6岁组对DNR的生物利用度高,代谢清除慢,提示男性及>6岁组可能更易出现毒副反应,可适当减少用量.

Relationship between pharmacokinetics and efficacy anti toxicity of daunorubicin in children with acute leukemia

Objective To study relationship between daunorubicin (DNR) pharmacokinetics and efficacy and toxicity in children with acute leukemia.Methods (1) The concentration of DNR in plasma of children with acute leukemia was determined by high performance liquid chromatography (HPLC)-fluorescence detection method.Plasma was sampled frequently from the start of the infusion till the end of 24 h.DNR pharmacokinetics was studied by determination of the concentrations.(2) Efficacy and toxicity were monitored in each period after chemotherapy.Laboratory studies included examination of bone marrow,white blood cell count,electrocardiogram,echocardiogram,myocardial enzymogram,the liver and kidney function.Results (1) DNR was eliminated from plasma in a two-compartment manner.The maximum concentration was seen 1-3 h after infusion.Cmax was 63.50 ug/L.Tmax was 1.45 h.The concentration decreased quickly to a low level of about 11.52 ug/L from the end of 2 hours infusion.There was a large inter-individual difference in pharmacokinetic parameters of DNR.The difference of CL was 9-fold,AUC and that of children younger than 6 years was 1.8 h(P<0.05);Cmax of children older than 6 years was 90.77 ug/L,younger than 6 years was 57.44 ug/L(P<0.05).Conclusion (1) There is a large inter-individual difference in pharmacokinetic parameters of DNR in children.It may predict individual variety of efficacy and toxicity.Therapeutic drug monitoring is important.(2) Male patients and children older than 6 years had a higher bioavailability and lower metabolism,toxicity may easily occur in such children,therefore they may need lower dose.