摘要
目的评价人组织型尿激酶型纤溶酶原激活剂(HTUPA)在SD大鼠体内的半衰期、组织分布及排泄。方法以125I为示踪剂标记药物HTUPA,SD大鼠单次静脉注射不同剂量的HTUPA,于给药后各时间点采集眼眶血样、尿粪样本和胆汁样本,以及不同时间点处死的大鼠脏器样本,以放射性同位素示踪结合三氯乙酸沉淀法定量检测血浆浓度,分析药物半衰期、组织分布及排泄率。结果大鼠静脉注射1、2和4 mg/kg的HTUPA,其药物浓度-时间曲线符合二室模型特征,平均分布半衰期(t1/2α)分别为(5.62±4.22)、(6.37±4.93)和(6.57±4.13)min;平均消除半衰期(t1/2β)分别为(49.21±19.36)、(41.17±18.50)和(43.68±28.67)min,且剂量与药时曲线下面积呈正相关(r=0.998 5);单次静脉给药2 mg/kgHTUPA,肝肾组织中含量最高,脑含量最低;96 h经尿液和粪便的累计排泄量占总给药量的79.08%和15.40%,24 h胆汁累计排泄量占总给药量的6.67%。结论 HTUPA作为新一代溶栓候选药,体内分布速度快,半衰期适合。
Abstract： Objective To evaluate the half-life, tissues distribution and excretion of human tissue urokinase type plasminogen activator （HTUPA） in SD rats. Methods Using 125^Ⅰ labeled HTUPA as a tracer, the samples of plasma, tissue, bile, urine and fecal were collected from the test rats at the various time points with various dosage after single- dose intravenous injection and measured by counting TCA-precipitable radioactivity. Half-life, tissue distribution and excretion rate were evaluated. Results The concentration-time curve of HTUPA was fitted to a two-compartment model after intravenous injection with the dosages of 1, 2 and 4 mg/kg, respectively; with the mean distribution half life （t1/α） of （5.62±4.22）, （6.37±4.93） and （6.57±4.13） min, respectively; Also, blood clearance showed elimination half life （t/2β） of （49.21±19.36）, （41.17±18.50） and （43.68±28.67） min, respectively. A linear relationship was found between the dose and area under the curve （AUCinf） with r=0.998 5. After the rats being injected with HTUPA of 2 mg/kg, the concentration of the HTUPA was higher in kidney and liver, and was lower in brain. Additionally, the excretion ratios of the HTUPA into urine and feces at 96 h were 79.08% and 15.40%, respectively, and it was 6.67% in bile at 24 h. Conclusion As a new candidate of thrombolytic drug, HTUPA has faster distribution speed and appropriate half life.
出处
《世界临床药物》
CAS
2012年第6期342-346,共5页
World Clinical Drug
基金
上海市科学技术委员会资助项目(编号:08DZ2291400)
