临床治疗剂量氯氮平人体内代谢机制研究

Metabolic mechanism of clozapine in clinical therapeutic dose

目的 本课题主要探讨临床治疗剂量氯氮平的代谢机制,为临床合理用药提供指导。方法 15例精神分裂症男性住院病人,单用氯氮平治疗,达到稳态浓度后,采用自身前后对照设计试验,研究氟西汀抑制前后氯氮平及其代谢产物药代动力学参数的变化及其与酶活性的相关性。CYP1A2、CYP3A4和CYP2D6的活性分别用咖啡因、咪达唑仑和右美沙芬探测。体内氯氮平及其代谢产物、咪哒唑仑及其代谢产物、尿中右美沙芬及其代谢产物用HPLC-MS测定。血中咖啡因及其代谢产物用HPLC-UV测定。数据用SPSS软件进行统计分析。结果 氯氮平合用氟西汀后,氯氮平的Cmax、AUC0-24显著增加,t1/2增加趋势,但没有显著性差异。代谢产物去甲氯氮平的AUC0～24显著降低,Cmax和t1/2无显著性差异。N-氧化氯氮平的Cmax和AUC0-24显著性降低,t1/2没有显著性差异。合用氟西汀前后CYP1A2活性无差异,CYP3A4和CYP2D6活性显著降低。合用氟西汀前后CYP1A2活性分别与合用氟西汀前后氯氮平的AUC0～24以及去甲氯氮平的AUC0～24相关,与N-氧化氯氮平的AUC0～24无显著相关。CYP3A4和CYP2D6活性与氯氮平、去甲氯氮平、N-氧化氯氮平的AUC0～24均无显著相关,但是合用氟西汀后CYP3A4活性变化与N-氧化氯氮平的AUC0～24变化显著相关。

OBJECTIVE To determine the metabolic mechanism of clozapine in clinical therapeutic dose. METHODS Fifteen male schizophrenic inpatients were recruited. All the patients received only clozapine to treat the disease. When the drug plasma concentration remained steady, CYP1A2, CYP3A4 and CYP2D6's probe drugs were givea We collected the blood and urine to study the pharmacokinetics of clozapine and detected the enzyme activities. Then clozapine and fluoxetine were co-administered daily at 8: 00 am for 3 days. On the 4th day, after giving clozapine and fluoxetine, blood samples were collected to study the pharmacokinetics of clozapine. At the same time, the probe drugs of CYP1A2, CYP3A4, and CYP2D6 were given to detect the enzyme activities. Plasma concentration of clozapine and its metabolites, as well as the urine concentration of midazolam, dextromethorphan and their metabolites were detected by HPLC-MS. Caffeine and its metabolites were detected by HPLC-UV. Data were analyzed by SPSS 10. 0. RESULTS After 3 days of coadministration, the Cmax and AUC0-24 increased significantly, t1/2 increased, but not significantly. AUC0-24 of demethyl-clozapine significantly decreased, but Cmax and t1\2 did not change. AUC0-24 and Cmax of N-oxide-clozapine significantly decreased, but t1/2 did not change much. The activities of CYP3A4 and CYP2D6 decreased, and CYP1A2 activity did not change. CYP1A2 activity was closely related to AUC0-24 of clozapine and demethyl-clozapine, but not to AUC0-24 of N-oxide-clozapine before and after the fluoxetine administration. CYP3A4 and CYP2D6 activities were not related to the AUC0-24 of clozapine and its metabolites before the fluoxetine administration, but the variations of CYP3A4 and CYP2D6 activities were related to those of the AUC0-24 of N-oxide-clozapine and demethyl-clozapine, respectively. CONCLUSIONS Clozapine is metabolized by demethylation and N-ox-idation in clinical therapeutic dose. Demethylation is the main pathway, which is catalyzed by CYP1A2. CYP3A4 and CYP2D6 may not be the important catalyzing enzymes in clozapine metabolism, but CYP3A4 and CYP1A2 play a role in catalyzing N-oxidation and demethylation.