小克银汉霉属微生物模型在体外药物代谢研究中的应用

药物代谢在药效和安全性评价中是非常重要的,而利用微生物转化为药物体外代谢模型则具有很多优势。小克银汉霉属的许多菌株具有与人体类似的Ⅰ相和Ⅱ相药物代谢酶,其微生物模型能对多种底物进行高效转化。本文对其在药物代谢方面的应用进行综述,并对其未来的发展进行了展望。     

离体肝灌流技术在药物和毒理学研究中的应用

肝脏在外源性化学物药物、毒物的代谢和处置中起着十分重要的作用,绝大多数药物和毒物进入体内经肝脏进行代谢后,转化为大极性的化合物排出体外或者被激活而导致毒性增加.在药物毒物代谢和毒理学研究中,原代肝细胞培养、肝组织切片、肝灌流、肝微粒体制备物温孵和基因工程细胞模型等体外实验被广泛应用[1-2].     

细胞色素P450与临床用药

目的介绍细胞色素P450的研究进展及其在临床药学工作实践中的指导意义。方法查阅国内外相关文献,进行综合、分析和归纳。结果临床药师观察到病人所表现的不同反应往往可用代谢转化的观点解释。根据细胞色素P450和药物的生物转化来选择合适的药物及合适的剂量将有助于最大程度地提高药物治疗效应,同时减少药物不良反应和毒副作用。结论临床药师要关注细胞色素P450和药物的代谢转化。     

体外Caco-2细胞模型在药物吸收中的应用进展

目的:介绍Caco-2细胞模型的特征及其在药物吸收中的应用.方法:分析国内外近期相关文献,对Caco-2细胞模型在药物吸收动力学中的研究进行概述.结果:Caco-2细胞模型用于药物动力学研究,可预测药物在体内的吸收和代谢.结论:体外Caco-2细胞模型在药物吸收过程的研究中有重要意义.     

丝状真菌产生的柳胺酚二相代谢产物研究

目的以微生物为模型 ,对柳胺酚的二相药物代谢产物进行研究。方法选用 7株丝状真菌为转化菌株 ,利用液相色谱 质谱联用技术对药物代谢产物进行检测。结果柳胺酚经过所选真菌转化后 ,形成葡萄糖结合物和五碳糖结合物 2种二相药物代谢结合产物 ,其中葡萄糖结合物为主要产物 ,产率最高可达 83 %左右 ;且无一相药物代谢产物形成。结论利用特定的微生物可建立研究柳胺酚二相代谢适宜的体外模型。     

Caco-2细胞在药物研究中的应用进展

目的Caco-2细胞模型特征及其在药物研究中的应用。方法概述了近年来Caco-2细胞模型在药物吸收机制、高通量筛选、药物相互作用、代谢及在药物剂型开发中应用情况。结果Caco-2细胞模型与整体吸收具有良好的相关性,可预测药物在体内的吸收、代谢规律。结论Caco-2细胞模型是药物体外研究的良好工具。     

肝体外代谢在中药活性成分研究中的应用进展

药物代谢系指药物进入体内后,在机体作用下发生的化学结构转化,即生物转化(Drug Biotransformation).转化在体内酶的作用下进行,能把外源性的物质进行化学处理,从而引起药物的药理活性和毒理活性的改变.近年来,模拟体内代谢过程的体外代谢研究方法迅速发展,通过离体器官、细胞或酶系统进行体外代谢研究[1].中药是一个复杂的体系,其有效成分或单体也作用于药物代谢酶系统,中药的体外代谢研究可以在短时间内得到大量的代谢产物,推断药物可能的代谢途径及参与代谢的酶,计算体内药物代谢的清除率,研究药物的相互作用[2],更好解释中药有效成分的作用机理,同时增强临床用药安全,为新药研究提供基础.     

药物体外ADME筛选模型

目前已有很多基于细胞水平的体外模型用于研究药物的吸收、分布、代谢、消除和药物毒性，以提高药物开发的成功率。如用于肠吸收研究的CaCo-2细胞模型、用于代谢研究的肝细胞模型及用于透血脑屏障研究的细胞模型。     

短刺小克银汉霉菌对维拉帕米转化的能力

目的　研究微生物模型对药物维拉帕米的代谢转化能力 ,并与人体内药物代谢进行比较。方法通过菌株筛选 ,确定以短刺小克银汉霉菌AS 3.15 3为转化菌株 ,采用液相色谱 质谱联用技术对代谢产物进行检测 ,并考察了微生物转化体系中影响代谢物产率的主要因素。结果　该霉菌转化维拉帕米形成C -N键和C -O键断裂的 10种氧化代谢产物。发现以pH 6 .5 ,底物浓度 0 .0 75 % ,转化反应持续 96h等条件 ,代谢产物的总产率 >95 % ,其中 1种主要产物N 去短链烷基维拉帕米的产率 >6 5 %。结论短刺小克银汉霉菌AS 3.15 3对维拉帕米具有与人体类似而且广泛的代谢途径 ,是研究人体药物代谢适宜的体外模型     

小克银汉霉菌对萘普生的微生物转化

目的：通过分离和鉴定萘普生由真菌转化生成的代谢产物,研究微生物转化和哺乳动物体内药物代谢之间的相似性．方法：选用3种小克银汉霉菌对萘普生进行微生物转化研究．采用液相色谱—质谱联用法检测代谢产物,并通过半制备高效液相色谱法分离出主要代谢物,经质谱和核磁共振光谱确证其结构．结果：萘普生被转化成去甲萘普生和去甲萘普生硫酸结合物,这两种代谢产物都是已知的哺乳动物代谢产物．其中去甲萘普生硫酸结合物是首次在微生物转化样品中发现．结论：小克银汉霉菌对萘普生的转化结果与哺乳动物的体内代谢有某些相似性,有可能成为一种新的体外模型进行药物代谢研究,用于预测和制备可能的药物代谢产物．     

细胞色素P450与药物代谢的研究现状

细胞色素P450(CYP)在众多中西药物代谢中起着非常重要的作用。本文综述了与药物代谢相关的CYP亚型、CYP与药物相互作用的关系及中药对CYP的影响，旨在合理解释和预测临床上药物间相互作用和药物不良反应等。同时选择适当的药物作为探针来评价CYP的活性，为实现临床个体化给药提供科学依据。     

Genotoxic evaluation of a vinifera skin extract that present pharmacological activities.

Toxicity of an alcohol-free hydro-alcoholic grape skin extract (GSE) obtained from red grapes Vitis labrusca (Isabel varietal) that present antihypertensive, vasodilator and antioxidant effects was estimated by different bioassays. Using the Salmonella/microsome assay for strains TA97, TA98, TA100 and TA102 no mutagenicity was detected for all tested concentrations (0.1-100 microg/ml), even with metabolization. Nevertheless, cytotoxicity was observed for TA97 and TA102 with and without metabolization and for TA100 with metabolization. The measurement of beta-galactosidase induction in the SOS-chromotest was positive only for Escherichia coli PQ37 when metabolization enzymes were present. Using Balb/c 3T3 fibroblasts, DNA strand breaks induction by GSE was also investigated by the comet assay and no significative difference was detected for treated and no treated DNA for 60 min. Our data suggest that GSE although no mutagenic presents cytotoxic activity.     

The metabolism of 8-methoxypsoralen by Saccharomyces cerevisiae. Evidence for an inducing effect of ethanol

The metabolism of 8-methoxypsoralen (8-MOP) by the yeast Saccharomyces cerevisiae has been investigated in order to determine if this cell system could provide a simple model to study the metabolism of new photosensitizing drugs in vitro. 8-MOP was found to be rapidly metabolized by S. cerevisiae in non growing conditions. A metabolite was detected which exhibits a structure similar to that of a metabolite previously isolated in dog and man. Ethanol showed a strong inducing effect on 8-MOP metabolization.     

长期吸入普米克都保对哮喘患者糖代谢的影响

目的探讨支气管哮喘患者长期吸入糖皮质激素对糖代谢的影响。方法检测54例哮喘患者在吸入普米克都保半年前、后的空腹血糖、餐后2 h血糖及糖化血红蛋白。结果吸入激素前、后,全部患者的空腹血糖、餐后2 h血糖及糖化血红蛋白无明显变化,无显著性差异(P>0.05)。结论长期吸入糖皮质激素对支气管哮喘患者的糖代谢无影响。     

Erythropoietin-loaded oligochitosan nanoparticles for treatment of periventricular leukomalacia

In this study, a single intraperitoneal injection of erythropoietin (EPO) loaded oligochitosan nanoparticles (epo-NPs) (average diameter 266 nm) was investigated as a treatment for periventricular leukomalacia (PVL). Nanoparticles were fabricated using a gelation technology process. PVL rats models were prepared to examine the therapeutic efficacy of epo-NPs and analyze the mechanism by which epo-NPs protect white matter. The metabolization of epo-NPs in the liver was also investigated. The pathology and behavioral data show that this single injection of a low quantity of epo-NPs had an excellent therapeutic effect on the rat model of PVL. The EPO release curve in phosphate buffered saline solution was a good fit with the zero-order kinetics distribution and was maintained at around 25% in 48 h. In vivo experiments demonstrated that 50 IU/kg epo-NPs had the same effect as a 5000 IU/kg direct injection of free EPO. Nanoparticles prolonged the time course of EPO metabolization in the liver and the stable release of EPO from the nanoparticles kept the plasma concentration of EPO at around 100 IU/ml during the 8-12h post-injection. Therefore, we suggest that oligochitosan based nanoparticles are an effective vehicle for drug delivery.     

Cadmium affects toxicokinetics of pyrene in the collembolan <Emphasis Type="Italic">Folsomia candida</Emphasis>

Since toxicity is time dependent, short-term toxicity tests may overlook mixture effects, because chemical accumulation within an organism takes time. We therefore studied the effects of cadmium on the toxicokinetics of pyrene and its metabolites in the soil-dwelling collembolan Folsomia candida exposed through Lufa 2.2 soil. Single pyrene was rapidly taken up and steady state was reached within the 337-h exposure period. Simultaneous exposure to cadmium significantly decreased the pyrene uptake and elimination rate, resulting in a prolonged half life. Kinetics of the first phase metabolite OH-pyrene was also significantly influenced by cadmium. Cadmium increased the hydroxylation rate of pyrene but slowed down its further metabolization, again resulting in a prolonged half life. We showed that pyrene accumulation and metabolization are significantly influenced by the presence of cadmium. Our results suggest that mixture effects may be dependent on exposure time.     

小檗碱对2型糖尿病大鼠骨骼肌糖脂代谢的影响及其机制

目的观察小檗碱对糖尿病大鼠骨骼肌病理结构改变和糖脂代谢紊乱的影响及其与PPARe α/γ/δ蛋白表达的关系。方法注射链脲菌素（35mg·kg^-1，i．p．）加高糖高脂饲料喂养16周建立2型糖尿病大鼠模型，随后16周每天分别拌食给予低中高剂量小檗碱（75、150、300mg·kg^-1）、非诺贝特（100mg·k^-1）和罗格列酮（4mg·k^-1），用HE染色检查骨骼肌结构病变、分光光度法测定肌糖元和甘油三脂含量及免疫组化检测PPAR α/γ/δ的表达。结果骨骼肌纤维在各组大鼠中仍正常分布，中高剂量小檗碱部分地改善糖尿病肌纤维的萎缩，增加肌糖元和降低甘油三脂含量（P〈0．01）。中高剂量小檗碱和罗格列酮都能明显降低糖尿病大鼠骨骼肌中PPARγ蛋白水平（P〈0．01），中高剂量小檗碱和非诺贝特能促进PPARα和PPARδ的表达（P〈0．01）。结论小檗碱调控骨骼肌PPARα/γ/δ蛋白的表达可能是其改善糖尿病骨骼肌纤维萎缩和糖脂代谢紊乱的机制之一。     

The Metabolic Fate of Deoxynivalenol and Its Acetylated Derivatives in a Wheat Suspension Culture: Identification and Detection of DON-15-O-Glucoside, 15-Acetyl-DON-3-O-Glucoside and 15-Acetyl-DON-3-Sulfate

Deoxynivalenol (DON) is a protein synthesis inhibitor produced by the Fusarium species, which frequently contaminates grains used for human or animal consumption. We treated a wheat suspension culture with DON or one of its acetylated derivatives, 3-acetyl-DON (3-ADON), 15-acetyl-DON (15-ADON) and 3,15-diacetyl-DON (3,15-diADON), and monitored the metabolization over a course of 96 h. Supernatant and cell extract samples were analyzed using a tailored LC-MS/MS method for the quantification of DON metabolites. We report the formation of tentatively identified DON-15-O-β-D-glucoside (D15G) and of 15-acetyl-DON-3-sulfate (15-ADON3S) as novel deoxynivalenol metabolites in wheat. Furthermore, we found that the recently identified 15-acetyl-DON-3-O-β-D-glucoside (15-ADON3G) is the major metabolite produced after 15-ADON challenge. 3-ADON treatment led to a higher intracellular content of toxic metabolites after six hours compared to all other treatments. 3-ADON was exclusively metabolized into DON before phase II reactions occurred. In contrast, we found that 15-ADON was directly converted into 15-ADON3G and 15-ADON3S in addition to metabolization into deoxynivalenol-3-O-β-D-glucoside (D3G). This study highlights significant differences in the metabolization of DON and its acetylated derivatives.