AP121在大鼠体内的组织分布研究

Study on tissue distribution of AP121 in rats

研究试图建立抗抑郁新药AP121在大鼠体内主要脏器组织的药物浓度检测方法,并探究其在大鼠体内的分布规律.选用健康SPF级SD大鼠24只,随机分为A、B、C3组,每组8只,雌雄各半,每组中随机选择1只大鼠作为空白对照(0 h),其他7只按19.32 mg·kg^-1灌胃给予AP121 Labrasol溶液后于1、4、9 h采集心脏、肝脏、脾脏、肺脏、肾脏组织样本,采用HPLC-MS/MS法检测5种脏器组织中AP121的浓度.结果显示,1、4、 9 h 3个时间点5种组织中的AP121浓度分布分别为:肝脏>肺脏>心脏>脾脏>肾脏,肺脏>肝脏>心脏>脾脏>肾脏,肝脏>肺脏>心脏>脾脏>肾脏;AP121在肺脏、心脏及肝脏中浓度个体差异大;肝脏中的AP121在1 h达最高浓度,其它4种脏器组织中AP121均在4 h达最高浓度,9 h各组织中的浓度大幅下降,且低于1 h时.分析结果表明,所建立的LC-MS/MS法测定大鼠5种主要脏器中AP121的分析检测灵敏、准确、可靠,可为该药系统的药代动力学评价提供技术支持;肝脏和肺脏可能是AP121的代谢转化器官或作用的靶器官,后续药物开发过程中,需关注药物对肺脏、心脏及肝脏的个体影响差异,且需重点关注药物对于肝脏和肺脏的影响.

A method is established for determining the concentration of AP121, a new anti-depressant, in the main organs and tissues of rats, to study on its distribution, and to explore the target organs of AP121. 24 healthy SPF SD rats were randomly divided into three groups: A, B and C, with 8 rats in each group, half male and half female. One rat in each group was randomly selected as the blank control group(0 h), the other 7 rats were given AP121 Labrasol solution at 19.32 mg·kg^-1, then the tissue samples of heart, liver, spleen, lung and kidney were collected at 1 h, 4 h and 9 h. The AP121 in 5 viscera tissues were detected by HPLC-MS/MS. As results, the concentration distribution of AP121 in five tissues at 1 h, 4 h and 9 h was as follows: liver > lung > heart > spleen> kidney, lung > liver > heart > spleen > kidney, liver > lung > heart > spleen > kidney;the individual difference of AP121 in lung, heart and liver was great;AP121 in liver reached the highest concentration at 1 h, and AP121 in other 4 organs reached the highest concentration at 4 h. At 9 h, the concentration in all tissues decreased significantly and was lower than at 1 h. The analysis results show that the LC-MS/MS method for the determination of AP121 in 5 main organs of rats is sensitive, accurate and reliable, which can provide technical support for the pharmacokinetic evaluation of AP121. Liver and lung may be the target organs of AP121. In the subsequent drug development process, attention should be paid to the individual effects of drugs on lung, heart and liver, and the difference should be serious in the effects of drugs on the liver and lungs.