【作者】 周茂金；

【导师】 刘昌孝； 钟大放；

【作者基本信息】 沈阳药科大学 ， 药物分析学， 2004， 博士

【摘要】 威替米星和反式白藜芦醇葡萄糖苷（PD-50）系正在研发的Ⅰ类候选新药，本文对威替米星和PD-50进行药物代谢和动力学研究，为其进一步研发提供依据。 威替米星（1-N-ethyl-verdamicin）是威达米星（verdamicin）在1-N位上引入一个乙基而合成的一种新型氨基糖苷类抗生素。根据该类抗生素化学修饰的构效关系，其分子结构中2-脱氧链霉胺的1-N位进行结构改造获得的新衍生物，往往较母核的毒性低，并对抵御耐药菌的钝化酶具有良好的作用。药效学实验也表明，威替米星抗菌谱广，杀菌力强，对临床分离的多种耐药菌显示良好的抗菌作用。 PD-50属于二苯乙烯苷类化合物，动物实验表明，PD-50在防止动脉内皮损伤性血栓形成，改善休克微循环，提高休克大鼠存活率，减轻缺血再灌注、自由基和内毒素造成的组织器官损伤，降血脂及抗脂质氧化和抗血小板聚集等方面具有良好的作用，提示PD-50可能成为治疗血栓性疾病及改善微循环等方面的新药。本论文主要研究工作如下： 一、米星在动物体内的药代动力学研究 威替米星在结构中缺乏发色团和荧光团，不能直接用紫外或荧光法进行检测。我们以2，4-二硝基氟苯（FDNB）为衍生化试剂，建立了测定生物样品中威替米星的HPLC-UV法，并用该方法对威替米星在大鼠和比格犬体内的药动学进行了研究。结果表明，大鼠和比格犬分别肌内注射威替米星后，吸收迅速且较完全，在大鼠和比格犬体内的绝对生物利用度分别为88.2％和79.0％。大鼠静脉注射给药后，威替米星迅速分布于全身大多数组织，各时间点均以肾脏中浓度最高。大鼠以20mg·kg^-1静脉注射威替米星后，主要以原形从尿中排泄，0～48h尿、粪和胆汁中原形药物的累积排泄率分别为81.1％、3.12％和1.44％，在大鼠体内未检测到代谢物。威替米星的血浆蛋白结合率较低，三个浓度的平均值为22.7％。大鼠静脉注射威替米星后，在低、中、高3个剂量范围内呈线性动力学特征。 二、氨基糖苷类抗生素及其FDNB衍生化产物的电喷雾离子阱质谱研究 在正离子检测方式下对氨基糖苷类抗生素及其FDNB衍生化产物进行ESI-MSⁿ分析，先用一级全扫描质谱方式获得待测物的准分子离子[M+H]⁺，然后分别对各准分子离子进行多级质谱分析，获得相应的碎片离子。在10种氨基糖苷类抗生素中，新霉素B由4个环组成，其余由3个环组成。在二级质谱分析中，新霉素B先脱去D环，其余9种均先脱去C环；在三级质谱分析中，新霉素B主要生成脱去C环的三级碎片离子，其它药物均可生成脱去B环或A环的三级碎片更多还原

【Abstract】 Both vertilmicin and Trans-resveratrol-3-O-glucoside （PD-50） are two new candidate drugs in the stage of preclinical development. In this paper, Preclinical pharmacokinetics of vertilmicin and PD-50 was investigated to provide bases for their investigations and developments in the future.Vertilmicin （1-N-ethyl-verdamicin） is a new semisynthetic aminoglycoside derived from verdamicin whose 1-N position of 2-deoxystreptamine is ethylated. Based on the structure-activity relationship of chemical modification of aminoglycosides, new derivatives which 1-N position of 2-deoxy-streptamine is modified with an ethyl have lower toxicities and stronger actions to resistance-causing enzymes than those of intact structures. Experiment results had also shown that vertilmicin had strong biological activities against broad spectra of Gram-negative and positive bacteria.PD-50, a kind of stilbene glucosides isolated from different plants, exhibited various pharmacological activities, including preventing thrombosis from arterial endothelial damage, improving microcirculation and increasing survival rate of shocked rats, alleviating tissue-organ damage induced by ischemia-reperfusion, oxygen free radical and endotoxin, decreasing hyperlipemia, suppressing lipid peroxide, reducing the serum triglyceride, anti-lipid oxidation, anti-platelet aggregation and so on. These pharmacological actions of PD-50 enable it to become a new characteristic drug in treatment of thrombotic diseases and microcirculation in shock.1. Study on pharmacokinetics of vertilmicin in animalsVetilmicin lacks any useful chromophores or fluorophores structurally, so detection is usually achieved only after pre- or postcolumn derivatization. The high-performance liquid chromatographic determination of vertilmicin in biological fluids was developed using l-fluoro-2,4-dinitrobenzene （FDNB） as derivatization reagent. The pharmacokinetics of vertilmicin in rats and dogs were examined by the developed HPLC-UV method. After vertilmicin was intramuscularly administered to rats or dogs, absorption of vertilmicin was rapid and complete. The absolute bioavailabilities of vertilmicin in rats and dogs were 88.2% and 79.0%, respectively. The tissue distribution of vertilmicin was investigated at 0.25, 1.0 and 4.0 h postdose in rats. When 20 mg·kg^-1 of vertilmicin was administered intravenously to rats, vertilmicin was rapidly distributed into the most of tissues,更多还原