摘要
目的研究氯氮平普通片和口腔崩解片在中国健康受试者的群体药动学特征,并探讨氯氮平口服吸收的特征。方法 42名健康男性志愿者按自身交叉试验方案设计,分别口服普通片和口腔崩解片各25 mg,分别于给药前和给药后0.25、0.5、0.75、1、1.5、2、3、4、6、8、10、12、24、36、60 h采集血样,用高效液相色谱串联质谱法测定血浆中氯氮平的浓度,并采用非线性混合效应模型法(NONMEM)对试验数据进行处理,求算2种剂型氯氮平的药动学参数。结果氯氮平体内药动学过程符合二室口服零级和一级平行吸收模型,一级吸收速度常数为0.43 h-1,零级吸收的比例为0.65%。一级吸收的滞后时间为0.471 h,零级吸收的滞后时间为0.123 h。群体药动学分布模型符合二室模型,氯氮平中央室的群体清除率和表观分布容积分别为43.6 L.h-1和13.5 L,外周室的群体清除率和表观分布容积分别为123 L.h-1和658 L,口腔崩解片和普通片的药动学参数间的差异无统计学意义。结论氯氮平的吸收同时存在一级和零级吸收模型,建立的模型具有较好的预测性,可为氯氮平普通片和口腔崩解片临床个体化治疗提供参考。
Objective To study the population pharmacokinetics of clozapine conventional tablets and disintegrating tablets in Chinese healthy volunteers.Methods Forty-two Chinese healthy volunteers were given 25 mg clozapine conventional tablets and disintegrating tablets respectively in a randomized two-way crossover design,and the plasma was collected at 0,0.25,0.5,0.75,1,1.5,2,3,4,6,8,10,12,24,36 and 60 h after administration.HPLC-MS/MS was used to determine the plasma concentration of clozapine.The population pharmacokinetic parameters were estimated by nonlinear mixed effect model（NONMEM）.Results A two-compartment model with zero-order and first-order parallel absorption process was built as the structural model.The first-order absorption rate constant was 0.43 h-1 and the fraction of zero-order absorption was 0.65%.The lag time of the first order absorption was 0.471 h,while it was 0.123 h for the zero-order absorption.The population pharmacokinetic distribution model was a two-compartment model,in which the population system clearance and central volume of distribution of clozapine were 43.6 L·h-1 and 13.5 L,respectively.The distribution clearance between central and peripheral compartments and peripheral volume of distribution were 123 L·h-1 and 658 L,respectively.No significance was found between the parameters of the conventional tablets and the disintegrating tablets.Conclusion The absorption process of clozapine was a parallel first-order and zero-order absorption model with adequate prediction.The population pharmacokinetic parameters of clozapine for conventional tablets and disintegrating tablets could be a reference for individual therapy.
出处
《广东药学院学报》
CAS
2013年第2期119-123,共5页
Academic Journal of Guangdong College of Pharmacy
基金
广东省重大科技专项(2011A080300003
2012A080204017)
广东省科技计划项目(00498500130062027)
