氯氮平及其代谢产物在精神科患者中的药代动力学：血浆蛋白结合与肾脏清除率。
Pharmacokinetics of clozapine and its metabolites in psychiatric patients: plasma protein binding and renal clearance.
作者信息
Schaber G, Stevens I, Gaertner H J, Dietz K, Breyer-Pfaff U
机构信息
Department of Toxicology, University of Tübingen, Germany.
出版信息
Br J Clin Pharmacol. 1998 Nov;46(5):453-9. doi: 10.1046/j.1365-2125.1998.00822.x.
AIMS
N-Desmethylclozapine and clozapine N-oxide are major metabolites of the atypical neuroleptic clozapine in humans and undergo renal excretion. The aim of this study was to investigate to what extent the elimination of these metabolites in urine contributes to the total fate of clozapine in patients and how they are handled by the kidney.
METHODS
From 15 psychiatric patients on continuous clozapine monotherapy, blood and urine samples were obtained during four 2 h intervals, and clozapine and its metabolites were assayed in serum and urine by solid-phase extraction and h.p.l.c. Unbound fractions of the compounds were measured by equilibrium dialysis.
RESULTS
The following unbound fractions in serum were found (geometric means): clozapine 5.5%, N-desmethylclozapine 9.7%, and clozapine N-oxide 24.6%. Renal clearance values calculated from unbound concentrations in serum and quantities excreted in urine were for clozapine on average 11% of the creatinine clearance, whereas those of N-desmethylclozapine and clozapine N-oxide amounted to 300 and 640%, respectively. The clearances of unbound clozapine and N-desmethylclozapine increased with increasing urine volume and decreasing pH. All renal clearance values exhibited large interindividual variations. The sum of clozapine and its metabolites in urine represented on average 14% of the dose.
CONCLUSIONS
Clozapine, N-desmethylclozapine and clozapine N-oxide are highly protein-bound in serum. Clozapine is, after glomerular filtration, largely reabsorbed in the tubule, whereas the metabolites undergo net tubular secretion. Metabolic pathways alternative or subsequent to N-demethylation and N-oxidation must make major contributions to the total fate of clozapine in patients.
目的
去甲氯氮平和氯氮平氮氧化物是抗精神病药物氯氮平在人体中的主要代谢产物，并经肾脏排泄。本研究旨在调查尿液中这些代谢产物的消除在多大程度上影响氯氮平在患者体内的整体转归，以及肾脏对它们的处理方式。
方法
选取15例接受氯氮平单一疗法的精神科患者，在4个2小时时间段内采集血样和尿样，采用固相萃取和高效液相色谱法测定血清和尿液中的氯氮平及其代谢产物。通过平衡透析法测定化合物的游离分数。
结果
血清中测得的游离分数如下（几何平均值）：氯氮平5.5%，去甲氯氮平9.7%，氯氮平氮氧化物24.6%。根据血清中游离浓度和尿中排泄量计算的肾脏清除率，氯氮平平均为肌酐清除率的11%，而去甲氯氮平和氯氮平氮氧化物分别为300%和640%。游离氯氮平和去甲氯氮平的清除率随尿量增加和pH值降低而升高。所有肾脏清除率值均存在较大的个体间差异。尿中氯氮平及其代谢产物的总量平均占剂量的14%。
结论
氯氮平、去甲氯氮平和氯氮平氮氧化物在血清中与蛋白高度结合。氯氮平经肾小球滤过后，大部分在肾小管中被重吸收，而代谢产物则经历净肾小管分泌。去甲基化和氮氧化之后的其他代谢途径或后续代谢途径必定对氯氮平在患者体内的整体转归起主要作用。
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