Laboratoire de Pharmacocinétique, Hôpital Carémeau, Nîmes, France.
Clin Drug Investig. 1998;16(1):35-43. doi: 10.2165/00044011-199816010-00005.
The pharmacokinetic profiles of clozapine and its main metabolite, norclozapine, were investigated in 18 chronic schizophrenic inpatients during long-term treatment.
Patients received stable daily doses (between 300 and 900mg) for at least 1 month. Plasma drug concentrations were determined by high performance liquid chromatography. The pharmacokinetic parameters were calculated from both noncompartmental and compartmental approaches with zero-order input rate using a kinetic model for simultaneous fit of clozapine and norclozapine (active metabolite) concentrations.
Large interpatient variations in pharmacokinetic parameters of the two drugs were observed. Plasma clozapine concentration peaked on average at 2 hours. The mean elimination rate constants from compartments 1 (k(10)) and 2 (k(20 ), elimination rate constant of norclozapine) were 0.087 and 0.156h(-1), respectively. The rate of formation of norclozapine, k(12), averaged 1.25h(-1). The mean fraction of the administered dose converted to norclozapine was estimated to be 66%. The apparent clearance of clozapine (CL/F) averaged 44.7 L/h and the volume of distribution (V(c)/F) was 7.00 L/kg. The pharmacokinetics of clozapine after multiple doses were linear over the range of clozapine plasma concentrations of 145 to 1411 microg/L.
This is the first study assessing the pharmacokinetic profile of clozapine plus norclozapine in plasma during long-term treatment. This pharmacokinetic model can be used to determine the population pharmacokinetic parameters of clozapine and norclozapine in order to optimise individual dosage regimens using a Bayesian methodology.
在 18 名慢性精神分裂症住院患者中，研究氯氮平及其主要代谢物去甲氯氮平在长期治疗中的药代动力学特征。
患者接受稳定的每日剂量（300 至 900mg 之间）至少 1 个月。通过高效液相色谱法测定血浆药物浓度。采用零级输入速率的同时拟合氯氮平和去甲氯氮平（活性代谢物）浓度的动力学模型，从非房室和房室两种方法计算药代动力学参数。
两种药物的药代动力学参数在患者间存在较大的个体差异。平均而言，氯氮平的血浆浓度在 2 小时时达到峰值。从房室 1（k10）和 2（k20，去甲氯氮平的消除速率常数）消除的平均速率常数分别为 0.087 和 0.156h-1。去甲氯氮平形成的速率，k12，平均为 1.25h-1。估计给予剂量转化为去甲氯氮平的平均分数为 66%。氯氮平的表观清除率（CL/F）平均为 44.7 L/h，分布容积（V（c）/F）为 7.00 L/kg。在氯氮平血浆浓度为 145 至 1411μg/L 的范围内，多次给药后氯氮平的药代动力学呈线性。
这是第一项评估长期治疗中氯氮平加去甲氯氮平在血浆中药代动力学特征的研究。该药代动力学模型可用于确定氯氮平和去甲氯氮平的群体药代动力学参数，以便使用贝叶斯方法优化个体剂量方案。
