摘要
本文采用体内、外相结合的实验方法,研究穿心莲内酯的体内转运与药动学规律。目的是为临床合理用药和新剂型开发提供理论依据。
药物的体内转运研究包括吸收、分布和排泄。本文采用大鼠原位肠道灌流法,研究穿心莲内酯的胃肠道吸收。结果穿心莲内酯主要在大鼠小肠中以被动转运方式吸收。这与测定的穿心莲内酯油水分配系数、pKa值、溶解度和稳定性,预测的药物吸收有较好的相关性。临床上联合用药不会产生竞争抑制作用。采用电穿孔技术和β-环糊精包合物,促进经皮吸收,效果较好。研制的包合物巴布剂,方法简便,工艺可靠,体外释放效果较好。定时取给药后大鼠的各组织器官和排泄物测定,结果穿心莲内酯在大鼠体内分布较广,其中在结肠、胃、十二指肠、肝和肾等器官分布较多。药物主要经肾排出体外。采用平衡透析法,测定穿心莲内酯的血浆蛋白结合率为5.86%。采用静脉注射给药,颈静脉定时取血,判断穿心莲内酯在大鼠体内的线性和非线性特征,结果在给药剂量范围内,药物表现为线性特征。药动学参数测定结果表明,增大剂量重复应用穿心莲内酯,不会引起蓄积中毒。
本文系统研究了穿心莲内酯的体内转运与药动学规律,成为本文的创新。电穿孔技术和β-环糊精包合物促进经皮吸收以及研制穿心莲内酯包合物巴布剂,也是本文的创新。
The medicinal plant Andrographis paniculata (Burm.f.) Nees plant is found in many Asian countries. Andrographolide(Andr) is one of the principal constituents of Andrographis paniculata (Burm.f.) Nees, used for the treatment of fever, cold, inflammation, diarrhea and other infectious diseases. Andrographolide also has many other bioactivities, such as antimicrobial activity , anti-platelet aggregation, inhibits growth of acute promyelocytic leukaemia cells by inducing retinoic acid receptor-independent cell differentiation and apoptosis , anti- HIV, choleretic action, anti-fertility Property , induces cell cycle arrest at G2/M phase and cell death in HepG2 cells via alteration and scavenge free radicals by donating the allylic hydrogen of the unsaturated lactone ring. In generally, Andrographolide take orally .However, Andrographolide have low aqueous solubility, bitterness and first pass effect lead to poor bioavailability when used for clinical treatment. As far as the factors affecting drug absorption, distribution, metabolism and excretion (ADME) are concerned, plasma membrane transport is one of the most important. The molecular mechanism of drug transport is very important as far as the bioavailability and targeting efficiency are concerned. This is the chemical structure of Andrographolide.Fig. 1. Chemical structure of Andrographolide
In the present study, we formulated Biopharmaceutics and Pharmacokinetics of Andrographolide. The main objective of the study was to research ADME of Andrographolide.Transdermal drug delivery was one of the principal constituents of disquisition.This study was conducted to determine parameters of physical and chemistry, the membrane transport of Andrographolide in rats to take orally and to evaluate infection of stomach content for absorption, distribution, Plasma Protein Binding , metabolism, and excretion of Andrographolide. Inclution compound ofβ-cyclodextrin and solid dispersion(SD)were preparated and dissolutions were determined. We found that dissolution of Inclution compound ofβ- cyclodextrin of Andrographolide was the fastest in its . In the present study absorption , distribution, metabolism, and excretion of Andrographolide in rabbits following muscle injection and trandermal drug delivery were evaluated. Time-course each tissue and blood and excreta were collected and determined. The drug concentration levels were determined by HPLC for Andrographolide. Andrographolide is first order precesses absorption in the small intestine. The absorption rate constant of Andrographolide was 0.0067h~(-1). Stomach content effected-absorption of Andrographolide in rats. Following transdermal drug delivery and muscle injection application, Transdermal drug delivery plasma levels of Andrographolide was high after the first 55 min. After muscle injection the drug concentration levels were lower than transdermal drug delivery. On the other hand, the absorbed Andrographolide did not accumulate in tissues; only a few of the administered dose was found in liver, spleen and kidney. Most of the applied Andrographolide was excreted in urine. This fact strongly suggests that transdermal drug delivery is better way than to take orally for Andrographolide. More studies in mammalian species are necessary in order to understand the pharmacokinetic behavior of Andrographolide. Plasma protein binding rate of Andrographolide was 5.86% .It is not strength .Electroporation to enable successful transdermal drug delivery for Andrographolide . We concluded that this study provided a scientific basis for the use of andrographolides in clinical therapy and offered important parameters that could be used in the design of a new class of preparations.
引文
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