大鼠体内杜鹃素及其高活性新结构衍生物的药代动力学比较研究

A comparative study on the pharmacokinetics of farrerol and its highly-active new derivative DJS-F in rats

目的建立高效液相色谱法(HPLC)同时测定大鼠血浆中杜鹃素及其新结构衍生物2-(呋喃-2-基)-5,7-二羟基-6,8-二甲基-2,3-二氢苯并吡喃-4-酮(DJS-F)的含量,并应用于两者药代动力学特性比较研究,为以杜鹃素为先导物的新型高效衍生物设计合成与药效学等提供科学依据。方法 SD大鼠分别尾静脉注射给予杜鹃素及其衍生物DJS-F(18 mg/kg,36 mg/kg),于预定时间点眼静脉丛取血,杜鹃素及其衍生物互为内标,HPLC法测定血浆中杜鹃素及其衍生物F含量,色谱柱:oddysill C18(4.6 mm×150 mm,5μm);流动相:甲醇-冰醋酸-水(65∶0.35∶34.65);体积流量:0.8 ml/min;紫外检测波长:217 nm。采用DAS2.1.1软件计算其药动学参数。结果所得不同时间点对应药物血浆浓度数据经软件自动拟合,得主要统计矩参数AUC(0-∞)分别为:杜鹃素2.311±0.778(18 mg/kg)、10.705±1.081(36 mg/kg)mg/L×h,DJS-F1.571±0.575(18 mg/kg)、7.130±2.232(36 mg/kg)mg/L×h;t1/2分别为:杜鹃素0.211±0.040(18 mg/kg)、0.097±0.023(36 mg/kg)h;DJS-F 0.216±0.125(18 mg/kg)、0.550±0.285(36mg/kg)h。结论本实验建立的HPLC法准确高效,具有良好的准确度、精密度及稳定性,可用于杜鹃素及其衍生物DJS-F血浆浓度测定。结果显示高剂量组DJS-F的AUC(0-∞)较其先导物杜鹃素显著下降,但半衰期t1/2显著延长,表观分布容积Vz显著提高,提示DJS-F在体内分布更加广泛。本实验所得数据可为杜鹃素的结构优化及药效学和毒理学评价提供参考。

Objective To establish a simple and sensitive HPLC method for simultaneous measurement of far-rerol and its new active derivative DJS-F in plasma and compare the pharmacokinetics of the two compounds in rats after intravenous administration, so as to provide evidence for design, biosynthesis and pharmacology of highly-active farrerol derivatives. Methods Farrerol and DJS-F were administered by i.v. injection via the lateral tail vein at the dose of 18 and 36 mg/kg, respectively. At scheduled time points, blood samples were collected in heparinized tubes from the orbital vein. The separation was achieved by HPLC on an oddysillC18 column （4.6 mm × 150 mm, 5μm） with a mobile phases composed of methanol-glacial acetic acid-water （65∶0.35∶34.65, V/V/V） at a flow rate of 0.8 ml/min, and the UV detection was used at 217 nm. Pharmacokinetics data was analyzed by DAS2.1.1 software. Results The AUC （0-∞） of farrerol and its derivative DJS-F were 2.311 ±0.778 and 1.571 ±0.575 mg/L ×h at the dose of 18 mg/kg;10.705±1.081 and 7.130±2.232 mg/×h at the dose of 36 mg/kg respectively. The t1/2 were 0.211±0.040 h vs 0.216± 0.125 h （18 mg/kg） and 0.097±0.023 h vs 0.550±0.285 h （36 mg/kg）, respectively. Conclusion A rapid and sensitive HPLC method was developed and validated to determine farrerol and its derivative DJS-F in rat plasma, with consid-erable accuracy, precision and stability. DJS-F has a significantly reduced AUC （0-∞）, but longer t1/2 and hightened ap-parent distribution volume compared with farrerol, suggesting a wider distribution in vivo. The pharmacokinetics data may be useful for further study of the structure optimization of farrerol and evaluation of toxicology and pharmacody-namics.