Pre-clinical pharmacokinetics of novel soybean iosflavone sulfonate

为寻找新的大豆异黄酮前药,采用建立的生物样品中药物浓度测定的液相色谱法对新型大豆异黄酮染料木素磺酸酯(GBS)进行前药判定以及大鼠体内药物动力学研究,以考察前药中染料木素(GE)的口服相对生物利用度是否改善.在大鼠体内药物代谢实验中,灌胃给予的大鼠血浆中能检测到GE的存在.在临床前药物动力学实验中,该前体药以40 mg/kg GE在大鼠体内的动力学过程符合一室模型.GBS中GE的相对口服生物利用度为原药的198.6％.结果表明:相对于原药GE,前药中GE的相对口服生物利用度得到极大地改善.该前药有进一步研究的意义.     

新型染料木素磺酸酯的前药判定与大鼠体内生物利用度

为寻找染料木素(GE)新的前药,采用建立的生物样品中药物浓度测定的液相色谱法对新型大豆异黄酮染料木素磺酸酯(GB)进行前药判定以及大鼠体内药物动力学研究,以考察前药中染料木素的口服生物利用度是否改善.在大鼠体内药物代谢实验中,灌胃给予GB的大鼠血浆中能检测到明显的GE.在临床前药物动力学实验中,该前体静注给药和以40 mg/kg灌胃药后,GE在大鼠体内的动力学过程均符合一室模型.GB中GE的相对口服生物利用度为原药的110.9％.研究表明,相对于原药GE,前药中GE的相对口服生物利用度达到预期的改善,该前药有进一步研究意义.     

黑龙江省野生和栽培大豆异黄酮与其组分相关性分析

利用高效液相色谱法（HPLC）检测了黑龙江省556份不同生态区以及不同类型大豆的异黄酮、大豆苷和染料木苷含量,其中野生大豆243份,栽培大豆313份。结果表明：野生大豆异黄酮含量高于栽培大豆,同时筛选出高异黄酮含量种质3份,低异黄酮含量种质2份。异黄酮、大豆苷和染料木苷含量三者问的相关分析表明,大豆异黄酮含量与大豆苷含量及染料木苷含量、大豆苷含量与染料木苷含量均呈极显著正相关。     

多孔淀粉负载青蒿素微球的溶出、生物利用度和组织分布研究

探讨多孔淀粉负载青蒿素微球(ART-PS)在体外溶出实验中,相比于青蒿素原药的溶出效果以及在大鼠体内的生物利用度和组织分布规律。在体外溶出实验中,分别在水、人工胃液和人工肠液三种溶出介质中,与青蒿素原药的溶出效果进行比较分析。在体内生物利用度实验中,通过对18只大鼠分别灌胃青蒿素原药与多孔淀粉负载青蒿素微球后,检测不同时间点的血药浓度,考察药物在大鼠体内的吸收和代谢差异。在组织分布规律的研究中,对98只大鼠分别灌胃多孔淀粉负载青蒿素微球和青蒿素原药,在不同时间点检测大鼠心、肝、脾、肺、肾、脑,共6个组织器官中的药物浓度。多孔淀粉负载青蒿素微球的体外溶出率在水、人工胃液、人工肠液中分别是青蒿素原药的4.04、3.59和3.82倍。多孔淀粉负载青蒿素微球在大鼠体内的血药浓度明显高于青蒿素原药,生物利用度提高为青蒿素原药的2.90倍。在组织分布的结果中,多孔淀粉负载青蒿素微球和青蒿素原药都主要分布在心脏和肝脏中,其中多孔淀粉负载青蒿素微球在不同时间各个组织中的相应含量都比原药高。多孔淀粉负载青蒿素微球相比于青蒿素原药,在体外的溶出效果更好,在体内的吸收释放效果更佳,在各组织器官中的药物含量明显高于原药,为解决青蒿素因难溶于水而在实际应用中受限提供了重要的理论依据。     

辅酶Q10/两亲性木聚糖纳米悬浮剂的制备以及生物利用度

研究一种新型共聚物负载辅酶Q10形成纳米悬浮剂能够增加CoQ10的水溶性,并且提高其口服生物利用度。本研究以槲皮素—木聚糖（QT-Xylan）共聚物偶联为基础进行合成,采用高剪切均质法进一步包载辅酶Q10,形成了一种新型载药纳米悬浮剂。采用单因素实验设计,并以粒径大小作为单因素实验的考察条件,影响其粒径大小的因素包括高压均质压力、高压均质次数、共聚物浓度、共聚物与CoQ10的质量比4个因素,并进行一系列体外实验评价。当均质压力为60 MPa,均质次数为7次,共聚物浓度为1 mg·mL^-1,共聚物与CoQ10的质量比为1∶1,是纳米悬浮剂的最佳制备工艺,此时粒径大小为166.7 nm。在最佳工艺条件下,在体外溶出实验中,包载CoQ10纳米悬浮剂的体外溶出率在人工胃液（SGF）和人工肠液（SIF）中分别是CoQ10原药的1.89和1.48倍。在体内生物利用度实验中,分别对大鼠灌胃CoQ10原药与载药纳米悬浮剂后,检测不同时间点的血药浓度,考察药物在大鼠体内的吸收和代谢情况,负载CoQ10的纳米悬浮剂在大鼠体内的血药浓度明显高于CoQ10原药,生物利用度提高为CoQ10原药的2.64倍。     

豆粕营养成分对蝙蝠蛾拟青霉发酵产物的影响

为探索培养基中的豆粕以及制备豆粕的原材料大豆对蝙蝠蛾拟青霉发酵产物的影响,我们比较了不同品种大豆和用其制成的豆粕的主要营养成分含量,包括粗蛋白、粗脂肪、6种微量元素（钙、镁、铜、锌、铁、锰）和总异黄酮（大豆苷、黄豆黄苷、染料木苷、大豆苷元、黄豆黄素、染料木素）,以及豆粕作为培养基对蝙蝠蛾拟青霉发酵产物的生物量和有效成分含量包括腺苷、腺嘌呤、虫草素和麦角甾醇的影响,结果表明大豆中钙和大豆苷与发酵产物中腺苷含量正相关。豆粕中钙、大豆苷、大豆苷元、染料木素与发酵产物中腺苷含量正相关;豆粕中钙、镁、大豆苷、大豆苷元、染料木素、总异黄酮与发酵产物中腺嘌呤含量负相关;豆粕中铁与菌丝体干重值正相关。结果表明,培养基中的豆粕和原料大豆主要营养成分含量对蝙蝠蛾拟青霉发酵产物品质有显著影响。     

兔肠道大豆异黄酮还原菌株的分离鉴定及其转化特性

【目的】从兔新鲜粪样中分离对大豆异黄酮黄豆苷原和染料木素具有转化作用的特定细菌菌株。【方法】在厌氧工作站内对獭兔新鲜粪样进行梯度稀释后涂板,挑取单菌落与底物黄豆苷原和染料木素分别厌氧混合培养,用高效液相色谱检测底物被转化情况。【结果】分离得到一株对大豆异黄酮黄豆苷原和染料木素均具有转化作用的革兰氏阳性严格厌氧细菌菌株AUH-JLR41(KJ188150)。根据产物的高效液相保留时间、紫外吸收图谱和质谱分析结果,将菌株AUH-JLR41代谢底物黄豆苷原和染料木素生成的产物分别鉴定为二氢黄豆苷原和二氢染料木素。经手性高效液相系统检测,产物二氢黄豆苷原和二氢染料木素均呈现两个等面积物质峰,表明这两个产物的对映体过量率均为0。通过转化动态研究发现,菌株AUH-JLR41分别在底物黄豆苷原和染料木素加入48 h和72 h后将底物全部转化为产物,该菌株能转化底物黄豆苷原和染料木素的最大浓度均为0.6 mmol/L。经BLAST比对,菌株AUH-JLR41的16S r RNA基因序列与斯奈克氏菌属菌株Slackia equolifaciens DZE(EU377663)的相似性高达99.6%。【结论】兔肠道分离的斯奈克氏菌属菌株Slackia sp.AUH-JLR41在厌氧条件下能将大豆异黄酮黄豆苷原和染料木素分别还原为二氢黄豆苷原和二氢染料木素。     

一种榄香烯口服微乳相对生物利用度的初步研究

目的:研究口服榄香烯微乳在大鼠体内的相对生物利用度。方法:大鼠口服给予榄香烯微乳、榄香烯乳剂后,在不同时间点采血,采用超快速液相色谱法检测血浆榄香烯的浓度,计算其药动学参数与相对生物利用度。结果:榄香烯微乳粒径为(67±13)nm;Zeta电位为(3.2±0.4)mv;pH值为5.16;粘度为6 mpa.s;表面张力为31.7 mN.m-1。榄香烯微乳中β-榄香烯含量为(8.273±0.018)mg.mL-1。榄香烯微乳相对生物利用度为163.1%。结论:大鼠口服榄香烯微乳与榄香烯口服乳相比其生物利用度有较大提高。     

光照对大豆幼苗组织中异黄酮含量和分布的影响

利用高效液相色谱（ＨＰＬＣ）测定了不同光照处理的大豆（Ｇｌｙｃｉｎｅｍａｘ（Ｌ．）Ｍｅｒｒｉ．）幼苗不同组织的异黄酮类含量。子叶中最高,叶片和根部相对较少。子叶的异黄酮以大豆甙和染料木甙及其丙二酰基结合体为主,且在光照条件下,异黄酮含量随光照时间的增加而显著升高;相反,黑暗中的异黄酮含量随苗龄的增加呈下降趋势;当子叶由黑暗转为光照处理以后,异黄酮含量同样随光照时间的增加而升高。在叶片和根部异黄酮含量和种类也因光照条件的不同而有很大差异。光照条件下,叶片中以染料木甙及其丙二酰结合体和黄酮芦丁为主,且随时间增加呈上升趋势;黑暗中的黄化叶片,则以大豆甙和丙二酰结合体为主,但随时间的变化不明显。在幼苗根部,黑暗条件下几乎检测不出异黄酮的存在;光照条件下,则可检测到５种异黄酮,其中以大豆甙元及其衍生物占主要部分。实验证实了光照对大豆异黄酮的积累有明显的促进作用     

丹贝发酵过程中大豆异黄酮组分与含量的变化

用HPLC方法检测大豆[Glycine max(Linn.)Merr.]发酵食品－丹贝的发酵过程中异黄酮各组分含量变化。在发酵的最初24h内,大部分异黄酮由糖甙转化成甙元,随着发酵时间的延长转化率逐渐降低,发酵终产物中异黄酮主要以大豆甙元和染料木素形式存在,发酵64h的丹贝中总异黄酮摩尔含量比未发酵的大豆高51．25％。     

Design and synthesis of factor Xa inhibitors and their prodrugs

In addition to our previously reported fluoro acrylamides Xa inhibitors 2 and 3, a series of potent and novel cyclic diimide amidine compounds has been identified. In efforts to improve their oral bioavailability, replacement of the amidine group with methyl amidrazone gives compounds of moderate potency (14, IC(50)=0.028 microM). In the amidoxime prodrug approach, the amidoxime compounds show good oral bioavailability in rats and dogs. High plasma level of prodrug 26 and significant concentration of active drug 26a were obtained upon oral administration of prodrug 26 in rats.     

Enhanced bioavailability of soy isoflavones by complexation with beta-cyclodextrin in rats

In order to improve the solubility and bioavailability of a soy isoflavone extract (IFE), inclusion complexes (IFE-beta-CD) of the isoflavone extract with beta-cyclodextrin (beta-CD) were prepared and studied for their solubility and bioavailability. The aqueous solubility of the complexes of IFE with beta-CD (2.0 mg/ml) was about 26 times that of IFE itself (0.076 mg/ml). The same dosages of IFE and IFE-beta-CD were orally administered to SD rats (Sprague-Dawley) on an isoflavone glycoside (IFG) basis (daidzin, genistin and glycitin), and the plasma concentrations of daidzein, genistein and glycitein were measured over time to estimate the average AUC (area under the plasma concentration versus time curve) of the isoflavones. After the oral administration, the AUC values for daidzein, genistein and glycitein were 340, 11 and 28 microg x min/ml, respectively. In contrast, the respective AUC values after the administration of IFE-beta-CD were 430, 20 and 48 microg x min/ml. The bioavailability of daidzein in IFE-beta-CD was increased to 126% by the formation of inclusion complexes with beta-CD, compared with that in IFE. Furthermore, the bioavailability of genistein and glycitein in IFE-beta-CD formulation was significantly higher by up to 180% and 170%, respectively, compared with that of IFE p=0.008 and p=0.028, respectively). These results show that the absorption of IFE could be improved by the complexation of IFE with beta-CD (IFE-beta-CD).     

Orally active factor Xa inhibitors: investigation of a novel series of 3-amidinophenylsulfonamide derivatives using an amidoxime prodrug strategy

A series of novel and potent 3-amidinophenylsulfonamide derivatives of factor Xa inhibitors were designed and synthesized using an amidoxime prodrug strategy. We focused on systemic clearance of parent compounds in rats, and performed in vivo pharmacokinetic screening. Incorporation of a carboxymethoxy group markedly improved systemic clearance (compound 43), and the related amidoxime 44 showed sufficient prodrug conversion. Compound 45, the double prodrug of 43, exhibited practicable bioavailability after oral administration in rats. Among the various compounds under investigation, KFA-1982 was selected for clinical development.     

Synthesis and evaluation of carbamate prodrugs of SQ109 as antituberculosis agents

The low bioavailability of SQ109 in rats, resulting from first-pass effect in the liver, may be remedied by prodrug strategy. Based on esterase-sensitive carbamate prodrug strategy, a novel series of prodrugs of SQ109 has been reported. Bioavailability of SQ109 after administration of prodrug 7a was 91.4% compared with 21.4% after oral administration of SQ109. After oral administration of compound 7a, the parent drug SQ109 exhibited preferential tissue distribution into lung and spleen, the target organs of tubercular infection and replication.     

Design, synthesis, and bioavailability evaluation of coumarin-based prodrug of meptazinol

Based on the known coumarin-based prodrug system, a new meptazinol (Z)-3-[2-(propionyloxy) phenyl]-2-propenoic ester (3) was designed and synthesized as prodrug to minimize the first-pass effect of meptazinol (1) and improve the oral bioavailability. The prodrug (3) showed a 4-fold increase in oral bioavailability over the parent drug meptazinol in rats.     

Synthesis and biological activation of an ethylene glycol-linked amino acid conjugate of cyclic cidofovir

Cidofovir (HPMPC) is a broad-spectrum anti-viral agent whose potential, particularly in biodefense scenarios, is limited by its low oral bioavailability. Two prodrugs (3 and 4) created by conjugating ethylene glycol-linked amino acids (L-Val, L-Phe) with the cyclic form of cidofovir (cHPMPC) via a P-O ester bond were synthesized and their pH-dependent stability (3 and 4), potential for in vivo reconversion to drug (3), and oral bioavailability (3) were evaluated. The prodrugs were stable in buffer between pH 3 and 5, but underwent rapid hydrolysis in liver (t(1/2) = 3.7 min), intestinal (t(1/2) = 12.5 min), and Caco-2 cell homogenates (t(1/2) = 20.2 min). In vivo (rat), prodrug 3 was >90% reconverted to cHPMPC. The prodrug was 4x more active than ganciclovir (IC50 value, 0.68 microM vs 3.0 microM) in a HCMV plaque reduction assay. However, its oral bioavailability in a rat model was similar to the parent drug. The contrast between the promising activation properties and unenhanced transport of the prodrug is briefly discussed.     

The effects of PGF1α, PGE2 and 16,16 dimethyl PGE2 on gastric emptying and small intestinal transit in rat

Prostaglandins are well known for their ability to stimulate contraction in gastrointestinal smooth muscle, yet very little information is available on how their activity affects propulsion . Thus, studies were undertaken to determine the effect of various prostaglandins on qastric emptying (GE) and small intestinal transit (SIT) in unanesthetized fasted rats. Rats were treated with intravenous, subcutaneous, or oral PGF_2α, PGE₂, or 16,16 dimethyl PGE₂ at various doses, followed 1 (intravenous), 20 (subcutaneous) or 10 (oral) mins later by intragastric ⁵¹Cr oxide in black ink. Forty-five mins later, rats were sacrificed by CO₂ asphyxiation, the pylorus clamped, and the gut excised. SIT was expressed as the percent of intestinal length traveled by the most distal portion of ink. GE was expressed as the percent of the ⁵¹Cr emptied into the intestines. If GE was affected by prostaglandin treatment, the experiments were repeated with rats pre-implanted with duodenal cannula. This preparation allowed the visual transit marker to be deposited directly into the dueodenum, thus avoiding acceleration or delay of SIT caused by fluctuations in GE. The results of these studies show that: (1) intravenous 16,16 dimethyl PGE₂ (5–50 μg/kg), but not PGF_2α or PGE₂, accelerates GE and delays SIT; (2) oral prostaglandin administration increases SIT; (3) oral 16,16 dimethyl PGE₂ delays GE; (4) subcutaneous 16,16 dimethyl PGE₂ accelerates, has no effect upon, or delays GE depending upon dose, but accelerates SIT at all doses tested; and (5) subcutaneous PGE₂ accelerates SIT while PGF_2α does not. Thus, the effect of prostaglandins on GE and SIT depends upon the dosage and route of administration as well as type of prostaglandin used.     

Investigation on recombinant hirudin via oral route

The possibility for oral administration of peptide recombinant hirudin variant (rHV2-K47) as an anticoagulant agent was evaluated in several aspects. The proteolytic properties of rHV2-K47 and its stability during storage were examined by in vitro experiments. Radiolabeled rHV2-K47 was infused into the duodenum of rats and rHV2-K47 absorbed into serum was shown to be intact by electrophoresis pattern. The in vivo coagulation time of blood from mouse was prolonged significantly after oral administration of rHV2-K47. The bioavailability (F) of rHV2-K47 via oral route reached 10.11% in comparison with intravenous administration as gold standard. All the results suggested that rHV2-K47 could be delivered successfully via the oral route.