氯氮平及其代谢产物在兔体内的死后分布

Postmortem distribution of clozapine and its metabolites in rabbits

目的建立氯氮平的新西兰大白兔染毒致死模型,观察氯氮平(CLP)及其代谢物在兔体内的死后分布规律。方法按LD50(270 mg.kg-1)与4 LD50(1 080 mg.kg-1)氯氮平给新西兰大白兔灌胃,待实验动物心跳呼吸等生命体征全部消失后,在死亡当时,迅速解剖动物,提取心血、尿、脑、心、肝、脾、肺、肾等组织,样本冷冻保存,经固相萃取提取后,LC/MS/MS定性、定量检测其中氯氮平(CLP)及其代谢物去甲氯氮平(DMCLP)、N-氧化氯氮平(CLP-NO)的含量。结果氯氮平及其代谢物的死后分布存在器官的依存性,肺、肝、肾等器官的分布浓度高,而玻璃体液及下肢肌分布浓度较低。随着染毒剂量的增加,CLP及其代谢物在组织中浓度(尿液除外)有所升高,CLP代谢物与原体浓度的比值随剂量的增加有所下降。结论氯氮平及其代谢物在新西兰大白兔分布不均匀,除常规的尿和血液可以作为分析的检材以外,肝、肺、肾等氯氮平及其代谢物富集的器官亦可作为检案的分析样本。氯氮平及其代谢物浓度与染毒剂量成正比,代谢物与原药浓度的比值与染毒剂量成反比。

Objective To estabish clozapine（CLP） infected death model in New Zealand white rabbits to observe the postmortem distribution of CLP and its metabolites.Methods New Zealand White rabbits were divided into 2 groups randomly,with the doses of LD50（270 mg.kg-1） and 4 LD50（1 080 mg.kg-1） of CLP to fill in the stomach.After entire stop of breathing and heartbeat and other vital signs,anatomy was done quickly at death time： the blood,urine,brain,myocardium,liver,spleen,lung,kidney and other tissues were frozen and stored,to detect the amount of CLP and its metabolites（DMCLP,CLP-NO） by LC-MS/MS qualitative and quantitative after solid phase extraction.Results The postmortem distribution of CLP and its metabolites were organ-dependent,the content of CLP and its metabolites in the lung,liver and kidney were high,but lower in vitreous humor and muscles of the lower limb.With the increase of infection dose,concentration of the CLP and its metabolites in tissues（except for the urine） was increased.The CLP metabolites and the original body concentration ratio decreased with increasing dose.Conclusion The distribution of CLP and its metabolites in New Zealand white rabbits are uneven.In addition to urine and blood which are routine samples,liver,lung and kidney where CLP and its metabolites tend to gather can also be tissue analysis samples.Concentration of CLP and its metabolites are proportional to the canister to dose.Metabolites and reversed-phased concentration ratio is inversely proportional to the canister to dose.