药物生物转化研究方法简述

目的概述药物生物转化的常用研究方法。方法查阅国内外文献,概括药物在体内生物转化的常用研究方法。结果与结论药物的生物转化主要在肝脏进行,也可在肝外如消化道、肺、皮肤、脑、鼻黏膜、肾脏等组织进行,且肝脏外器官的生物转化活性比肝脏要低得多,药物生物转化的常用研究方法有:传统体内方法、微透析取样研究法、药物肝代谢研究法、药物胃肠道生物转化研究等。     

制药工业中甾体微生物转化的应用浅析

现代科技不断更新发展,许多新的技术逐渐成熟并应用于日常生活之中。而在现代医药工业领域中,许多企业开始使用微生物转化技术加以产品的制作,这种微生物转化技术的应用占有极为明显的优势。本文主要阐述了微生物的转化所表现出来的积极作用,同时也介绍了微生物转化技术在制药工业中的应用。     

哺乳动物代谢的微生物模型

由于哺乳动物产生的药物代谢产物往往仅有痕量,故难以测定其化学结构和生物活性。本文综述应用微生物模拟哺乳类代谢过程,使产生足量的药物代谢产物,以供用于药理研究。微生物转化微生物转化即指微生物系统对各种化学物     

短刺小克银汉霉AS 3.970对白鲜碱的微生物转化

目的 采用短刺小克银汉霉AS 3.970(C.blakesleana AS 3.970)对白鲜碱展开微生物转化研究。方法 利用30株丝状真菌对白鲜碱进行微生物转化,筛选出转化效果好的菌株;然后在该菌株微生物转化试验中考察接种量、转化温度、培养基pH值、转化时间等不同因素对白鲜碱微生物转化作用的影响,选择出最优的转化条件;在最优转化条件下,规模制备白鲜碱的微生物转化产物并进行结构鉴定。结果 短刺小克银汉霉AS 3.970对白鲜碱的微生物转化效果好,在微生物转化研究中发现白鲜碱转化的最优条件是转化温度为28℃,培养基初始pH值为7.0,最适接种量5%(体积分数),转化时间为7 d;通过分离纯化和结构鉴定,最终得到两个主要转化产物,分别是4-甲氧基-2,3-二氢呋喃喹啉与3-(2-羟乙基)-4-甲氧基喹啉酮。结论 通过微生物转化技术可以对白鲜碱进行微生物结构修饰。     

短刺小克银汉霉AS 3.970对川丁特罗的微生物转化

目的对川丁特罗进行微生物转化研究。方法利用短刺小克银汉霉Cunninghamella.blakesleana AS 3.970对川丁特罗进行微生物转化,通过柱层析、液相色谱-质谱及核磁技术对川丁特罗微生物转化产物进行分离与鉴定。结果短刺小克银汉霉Cunninghamella.blakesleana AS 3.970转化川丁特罗累计获得三个转化产物,分别是川丁特罗芳香羟胺代谢物、川丁特罗叔丁基羟基取代代谢物和1-羧基川丁特罗。结论通过微生物转化技术可以对川丁特罗进行微生物结构修饰。     

新抗生素的研究进展

综述了国内外在新抗生素研究方面的进展,包括:开辟新的微生物来源;设计、应用各种新的筛选模型和方法;化学修饰;微生物转化;生物合成的方法和技术;细胞融合技术以及基因重组技术。     

中药微生物转化的现状及前景

中药是中华民族的瑰宝,经历了数千年的传承与发展,对人民的防病治病做出了不可磨灭的贡献,近年来各种疑难杂症频繁出现,中药的发展潜力更是受到了世界人民的关注和重视。伴随着中药现代化战略的实施,中药的发展也迎来了新的机遇与挑战。微生物转化是当前中药现代化研究的热点之一,就微生物转化的概念、特点以及微生物转化技术在中药中的应用现状进行概述,并对中药微生物转化的发展前景做展望。     

甾体药物生物转化体系的研究进展

微生物转化是许多甾体药物或其中间体合成路线中不可或溶解度极低.因此,创建合理有效的生物转化体系对提高底物有效浓度,进而提高转化率具有重要意义.本文从增加底物溶解度,解除底物(产物)抑制,改变细胞膜(细胞壁)通透性等三方面就该领域的研究概况进行综述.     

肝脏灌流技术及其在药物研究中的应用进展

肝脏灌流技术在药物研究的应用已有几十年历史。与其他体外方法相比 ,肝脏灌流具有显著的优点 ,是研究药物代谢与生物转化、药物相互作用、药物对肝脏作用的理想模型 ,至今仍在药物研究中发挥重要作用。该文对该技术及其在药物研究中的应用进展进行了综述     

微生物转化在现代中药研发中的应用

微生物转化是指利用微生物的一种或多种酶,在一定条件下,把一种化合物转变为结构相关的有经济价值的另一种化合物。近年来,微生物转化技术越来越多地应用于中药的研发,目的在于提高中药药效,降低毒性,去除杂质,帮助有效成分在体内代谢,产生新的活性成分等。此外,微生物转化具有反应类型广、特异性强、副产物少、反应条件温和可控、环保无污染等优点,在中药转化领域具有独特优势。本文总结了近年来微生物转化技术在中药研发中的应用情况并进行了展望。     

手性药物代谢研究中的对映体分析方法

生物体是一个复杂的手性系统,其手性特征促使了它们与手性化合物的立体选择性相互作用。手性药物的两个对映体在吸收、分布、代谢、排泄过程中存在着动力学差异,尤其是代谢行为。因此,在手性药物代谢的研究中,同时测定对映体是极为重要的。本文通过综述近年来发表的众多文献,详细论述了在药物代谢中应用广泛的手性分析方法,包括高效液相色谱、高效液相色谱-质谱联用、气相色谱和毛细管电泳等。     

Enantiomeric Resolution of Drug Compounds by Liquid Chromatography

Novel techniques have recently emerged to separate chiral drug compounds into pure enantiomers. The mechanism, experimental difficulties, and applicability of these methods can vary greatly, and the choices involved are not straightforward. The most significant new advances in the field of chiral separations have come from work done with liquid chromatographic systems and chiral stationary-phase columns. This review describes several commonly used approaches to chiral separation, diastereomeric derivatization, chiral mobile-phase additives, and three major types of chiral stationary phases. Although no single method can be judged superior for every drug application, it appears that chiral stationary phases have received the most attention recently and they are emphasized here.     

Stereoselectivity in drug metabolism

Many chiral drugs are used as their racemic mixtures in clinical practice. Two enantiomers of a chiral drug generally differ in pharmacodynamic and/or pharmacokinetic properties as a consequence of the stereoselective interaction with optically active biological macromolecules. Thus, a stereospecific assay to discriminate between enantiomers is required in order to relate plasma concentrations to pharmacological effect of a chiral drug. Stereoselective metabolism of drugs is most commonly the major contributing factor to stereoselectivity in pharmacokinetics. Metabolizing enzymes often display a preference for one enantiomer of a chiral drug over the other, resulting in enantioselectivity. The structural characteristics of enzymes dictate the enantiomeric discrimination associated with the metabolism of chiral drugs. The stereoselectivity can, therefore, be viewed as the physical property characteristic that phenotypes the enzyme. This review provides a comprehensive appraisal of stereochemical aspects of drug metabolism (i.e., enantioselective metabolism and first-pass effect, enzyme-selective inhibition or induction and drug interaction, species differences and polymorphic metabolism).     

The significance of chirality in drug design and development

Proteins are often enantioselective towards their binding partners. When designing small molecules to interact with these targets, one should consider stereoselectivity. As considerations for exploring structure space evolve, chirality is increasingly important. Binding affinity for a chiral drug can differ for diastereomers and between enantiomers. For the virtual screening and computational design stage of drug development, this problem can be compounded by incomplete stereochemical information in structure libraries leading to a "coin toss" as to whether or not the "ideal" chiral structure is present. Creating every stereoisomer for each chiral compound in a structure library leads to an exponential increase in the number of structures resulting in potentially unmanageable file sizes and screening times. Therefore, only key chiral structures, enantiomeric pairs based on relative stereochemistry need be included, and lead to a compromise between exploration of chemical space and maintaining manageable libraries. In clinical environments, enantiomers of chiral drugs can have reduced, no, or even deleterious effects. This underscores the need to avoid mixtures of compounds and focus on chiral synthesis. Governmental regulations emphasizing the need to monitor chirality in drug development have increased. The United States Food and Drug Administration issued guidelines and policies in 1992 concerning the development of chiral compounds. These guidelines require that absolute stereochemistry be known for compounds with chiral centers and that this information should be established early in drug development in order that the analysis can be considered valid. From exploration of structure space to governmental regulations it is clear that the question of chirality in drug design is of vital importance.     

An evaluation of four commercial HPLC chiral detectors: a comparison of three polarimeters and a circular dichroism detector

With increasing frequency, new drug candidates being introduced into pharmaceutical drug pipelines are chiral. Often only one enantiomer exhibits the desired biological activity and the other enantiomer may exhibit undesired side effects, thereby making chiral purity an important parameter. The introduction of chiral analysis adds additional complications in drug development. The pharmaceutical industry is constantly striving to streamline processes and improve efficiencies in an effort to move molecules to market quickly. In order to simplify the process of chiral method development, chiral screening can be set up, however a successful chiral screen depends on optimizing two factors: the column and the detector. The following work investigated the second factor and evaluated two types of commercially available chiral detectors for their possible use in chiral method development and screening: polarimeters and circular dichroism (CD) detectors. Linearity, precision, and the limit of detection (LD) of six compounds (trans-stilbene oxide, ethyl chrysanthemate, propranolol, 1-methyl-2-tetralone, naproxen, methyl methionine) on four commercial detectors (three polarimeters and one CD detector) were determined experimentally and the limit of quantitation (LQ) calculated from the experimental LD. Trans-stilbene oxide worked well across all the detectors, showing good linearity, precision and low detection limits. However, the other five compounds proved to be more discriminating and showed that the circular dichroism detector performed better as a detector for chiral screens, over the polarimeters.     

手性药物的立体选择性药物动力学

人体的手性环境造成了手性药物对映体的立体选择性药物动力学。由于体内生物大分子常常具有不同的立体构型,药物分子空间排列上的微小改变,可导致与生物大分子亲和力的明显差异,对映体之间表现出不同的药物动力学特征。药物动力学的立体选择性表现在手性药物的吸收、分布、代谢和排泄4个过程的差异,本文对影响这些差异的因素进行逐一的分析。     

超临界流体色谱法分离手性药物

综述了超临界流体色谱在手性药物分离方面的研究和应用，介绍了超临界流体色谱手性分离的分离方式、色谱装置及操作条件。超临界流体色谱是一种很有潜力的色谱分离技术，具有高效、快速等特点，可以有效地弥补高效液相色谱和气相色谱在手性药物分离方面的不足。     

手性药物对映体在药效学与药代动力学的相互作用

当手性药物以外消旋体供药用时，其对映体间就可能发生药效学和药代动力学的相互作用。本文综述了手性药物对映体间的药效学和药代动力学相互作用及其对手性药物药效学和药代动力学立体选择性的影响。     

Demonstrative validation study employing a packed column pressurized fluid chromatography method that provides assay, achiral impurities, chiral impurity, and IR identity testing for a drug substance

Assay development, assay validation, and documentation are reported here for a single packed column pressurized fluid chromatographic/ultraviolet (UV) method that provides: (1) simultaneous detection and quantification for the chiral drug, the chiral impurity and seven achiral impurities; and (2) a Fourier transform infrared (FT-IR) spectrometric identification test result for the Searle drug substance sample, xemilofiban. The separation is achieved in less than 30 min with three columns in tandem and a gradient of CO₂–CH₃OH. The post-column flow is split between UV (assay) and FT-IR (identification). Precision and accuracy are consistent within figures of merit obtained by liquid chromatographic-ultraviolet assays on analogous drug substances. The reported procedure combines three typical drug substance tests into one test (e.g. chiral impurities, achiral impurities, and infrared identification).     

手性药物高效毛细管电泳拆分方法的研究进展

高效毛细管电泳法（high performance capillary electrophoresis,HPCE）在手性药物拆分领域得到了广泛的应用。目前,手性离子液体用于毛细管电泳拆分手性药物时,常与环糊精（CD）类手性选择剂构成二元体系产生协同作用,增强了手性离子液体潜在的手性拆分能力。依据对映体拆分的手性选择剂的种类及浓度、缓冲液的浓度和pH、电泳工作电压和温度,选出手性拆分的最佳条件。综述手性药物的发展以及应用HPCE拆分手性药物的文献资料,并对其研究的新进展作了分析。