染料木黄酮在Beagle犬体内代谢动力学的剂量依赖性研究  

Dose-dependent pharmacokinetic study of genistein in Beagle dogs

作　　者：周四元[1] 梅其炳[1] 王汝涛[1] 王庆伟[1] 杨志福[1] 王四旺[2] 

机构地区：[1]第四军医大学药理学教研室,陕西西安710032 [2]第四军医大学药物研究所,陕西西安710032

出　　处：《药学学报》2005年第6期553-556,共4页Acta Pharmaceutica Sinica

基　　金：国家高技术研究发展计划(863计划)项目(2003AA2Z347C).

摘　　要：目的　研究不同剂量染料木黄酮(genistein)在Beagle犬体内的药代动力学特征。方法　将染料木黄酮制成混悬液,按2 67, 5 34及10 68mg·kg-1给Beagle犬灌胃,于灌胃后不同时间在犬前腿部静脉采抗凝血标本,用葡糖醛酸酶溶液处理血浆。采用反相高效液相色谱法测定血浆中母体药物及葡糖醛酸结合型药物浓度,血浆药物浓度时间数据用3P97药代动力学软件分析。结果　染料木黄酮在Beagle犬体内过程符合二室开放模型,当剂量为2. 67mg·kg-1时,母体药物MRT为52 9min,AUC为6 .7mg·min·L-1,葡糖醛酸结合型药物AUC为33 9mg·min·L-1;当剂量为5 .34mg·kg-1时,母体药物MRT为224 .8min,AUC为26. 1mg·min·L-1,葡糖醛酸结合型药物AUC为70 .1mg·min·L-1;当剂量为10 68mg·kg-1时,母体药物MRT为267. 7min,AUC为33 .2mg·min·L-1,葡糖醛酸结合型药物AUC为140. 5mg·min·L-1。结论　染料木黄酮首过代谢突出,血浆中药物主要以葡糖醛酸结合形式存在。在一定范围内随给药剂量增加,母体药物的吸收量趋于饱和,药物的血浆消除半衰期延长。Aim To study the pharmacokinetics of genistein at different doses in Beagle dogs. Methods Suspended in 0.5% CMC-Na solution, genistein was orally administered to Beagle dogs at doses of 2.67, 5.34 and 10.68 mg·kg^-1. At various time intervals, 1.5 mL of blood was drawn from the femoral vein of dogs in their front legs. The plasma was treated with β-glucuronidase. The genistein in plasma was extracted twice by vortexing with 2.0 mL mixture of methyl tert-tubtyl ether and pentane (~v/v=8∶2). The organic phase was removed into the tubes and then evaporated in ventilation cabinet. The residue was dissolved in 50 μL of methanol. 20 μL solution was drawn and detected by high-performance liquid chromatography. The pharmacokinetic parameters were calculated by 3P97 software. Results The plasma drug concentration-time data were fitted to the two-compartment model. When the dose was 2.67 mg·kg^-1, the MRT and AUC of parent compound were 52.9 min and 6.7 mg·min·L^-1, respectively. When the dose rose to 5.34 mg·kg^-1, the MRT and AUC of parent compound became 224.8 min and 26.1 mg·min·L^-1, respectively. However, when the dose increased to 10.68 mg·kg^-1, the MRT and AUC of parent compound increased to 267.7 min and 33.2 mg·min·L^-1, respectively. The AUC of glucuronidated genistein was 33.9, 70.1 and 140.5 mg·min·L^-1 at the dose of 2.67, 5.34 and 10.68 mg·kg^-1, respectively. Conclusion Due to significant first pass metabolism, the drug was mainly existed in the form of glucuronidated genistein in the plasma. With the increase of dose, the absorption of genistein became saturated and the half life prolonged.

关 键 词：染料木黄酮 药物代谢动力学 高效液相色谱 半衰期 

分 类 号：R969.1[医药卫生—药理学]