【作者】 田娟；

【导师】 丁劲松；

【作者基本信息】 中南大学 ， 药剂学， 2010， 硕士

【摘要】 目的解郁胶囊是以紫苏(Perilla)活性部位为主要成分的具有抗抑郁作用的新型中药制剂,熊果酸是主要活性成分和质量控制指标。临床前药效学及毒理学研究表明,解郁胶囊具有良好的抗抑郁效果及极低的毒副作用,有望成为一个新型的抗抑郁药物。本课题首次研究了解郁胶囊中熊果酸在健康成年志愿者体内的药代动力学,为解郁胶囊的Ⅱ期临床安全、合理的给药方案设计提供依据。方法与结果通过单次给药和多次给药试验考察解郁胶囊在健康人体的药动学特征。单次给药：采用三向交叉拉丁方设计。全部受试者分为男、女两个区组,随机进入6个试验组,每组受试者每周期试验时分别接受低、中、高(40,80,120 mg)剂量的试验制剂,在规定时间抽取静脉血,中剂量组受试者在给药前采集空白尿样并排空膀胱,于给药后分时间段收集尿样。多次给药：每名受试者每次给予40 mg的试验制剂,每日两次,连续给药至第6日晨。于规定时间抽取肘静脉血。所采集血样立即离心分离血浆,冷冻保存待测。血样和尿样中熊果酸浓度以新建立的HPLC-MS/MS法测定。方法学建立与验证表明血浆中内源性物质及杂质不干扰样品峰,线性范围为0.86～110.00 ng·mL-1,萃取回收率大于68.01%,批间和批内的变异系数小于11.74%。符合药代动力学生物样品分析的要求。血药浓度-时间数据应用DAS ver2.1 (Drug And Statistics for Windows)软件进行参数计算,获得各剂量组熊果酸的药动学参数。统计分析结果表明①熊果酸在体内的吸收呈非线性特征,Cmax、AUC0-24、AUC0-∞在给药剂量40-80 mg范围内,随剂量增加而增加,80-120 mg范围内与剂量不相关。t1/2与剂量不相关。②单次给药(40 mg)和多次给药的药代动力学参数lnAUC0-24、lnAUC0-∞、Cmax、V/F、CL/F、tmax、t1/2、MRT0-24之间的差异均无统计学意义,表明多次给药不影响药物的代谢消除,无药物蓄积。③尿样中熊果酸浓度均低于定量下限。结论单次口服解郁胶囊后,熊果酸在体内的吸收呈非线性特征,给药剂量高于80 mg时候,吸收呈饱和状态。熊果酸经肾排泄的原型药物很少。解郁胶囊多次给药在体内无蓄积作用。结合耐受性试验结果,建议Ⅱ期临床试验的给药方案是每次40 mg,一日两次,如需要增加剂量,则单次给药最大剂量为80 mg,日最大剂量不超过120 mg。更多还原

【Abstract】 OBJECTIVEJieyu Capsule is a new antidepressant Chinese medicine preparation with Perilla active site as the main component in which ursolic acid is the major effective constituent and quality control index. Preclinical pharmacodynamics and toxicological studies showed that Jieyu Capsule had an effective antidepressant and very low toxity, and it was expected to be a novel antidepressant drug. This research subject was the first time to study the pharmacokinetic parameters of ursolic acid in Jieyu Capsule in Chinese healthy adult volunteers and provide experimental basis for a safe and reasonable dosage regimen applicated in Phase II clinical research.METHOD AND RESULTSStudy the Pharmacokinetics of Jieyu Capsule in healthy volunteers in single dose and multiple dose trials. Single dose trial:A 3*3 Latin square design with a wash out period of 7 days was applied in this test. All volunteers were separated into male and female blocks, and then both were divided into six experimental groups randomly. Volunteers in each group were treated with low, middle and high (40 mg,80 mg,120 mg) dose of Jieyu Capsule respectively. Blood samples were collected at different time points before and 0.33,0.67,1.0,1.5,2.0,2.5,3.0,4.0,6.0,8.0,10.0,12.0,24.0 h after the drug administration in each phase. Volunteers treated with middle dose of Jieyu Capsule collected blank urine samples before administration and then evacuated bladder, and continuely collected urine samples in different time after administration. Multiple dose trial:Volunteers were administered with 40mg dose of Jieyu Capsule respectively at 7:30 and 19:30 in 5 consecutive days and the 6th morning. Blood samples were collected in the 4th,5th,6th morning before drug administration and 0.33,0.67,1.0,1.5,2.0,2.5,3.0,4.0, 6.0,8.0,10.0,12.0,24.0 h after drug administration in the 6th day. After centrifugalization, the plasma samples were freezed until analysis.A simple, sensitive HPLC-MS/MS method was developed for the quantitative determination of ursolic acid in human plasma and urine samples. The endogenous substances in plasma did not interfere with drug peak, and the linear range was 0.86～110 ng·mL-1. Extraction recoveries were more than 68.0%, variation coefficients of inter-batch and intra-batch were less than 11.7%. All the results were consistent with demands of biological samples analysis in pharmacokinetics research.DAS ver2.1 (Drug And Statistics for Windows) software was applied for model fitting and parameter calculation. Statistics results show that:①The absorbtion of ursolic acid in healthy volunteers showed nonlinear characteristics:in the dose range of 40-80 mg, AUC0-24, AUC0-∞, Cmax increased with the dose, while in the dose range of 80-120 mg, AUC0-24, AUC0-∞, Cmax showed no relationship with dose. t1/2 was not correlated with dosage.②lnAUC1-24, lnAUC0-∞, V/F, CL/F, Cmax, t1/2 and MRT0-24 of ursolic acid had no significant difference between the single dose and multiple dose of Jieyu Capsule, which showed no effect in metabolism and elimination and no drug accumulation of ursolic acid in healthy volunteers after administrated with multiple dose.③All the concentration of ursolic acid in urine samples were lower than the low limit of quantification.CONCLUSIONThe absorbtion of ursolic acid in healthy volunteers showed non-linear characteristics after single dose administration of Jieyu Capsule, and was in saturation when the dose higher than 80 mg. Ursolic acid was rarely excreted through kidneys with prototype drug. And no drug accumulation of ursolic acid was observed in healthy volunteers after administrated with multiple dose. Combined with the results of tolerance test, the better dosage regimen of Jieyu Capsule should be 40 mg each time and twice a day. If there is a need to increase the dosage, the largest single recomended dose is 80 mg, the daily maximum recomended dose is no more than 120 mg.更多还原