手性药物代谢动力学的立体选择性

手性是生物体系的一个基本特征。手性大分子物质,如酶、载体、受体、血浆蛋白和多糖等构成了生物体的手性内环境。在体内,手性药物对映体与生物大分子间相互识别、相互作用的立体选择性导致了手性药物在药代动力学方面的立体选择性,其主要表现在手性药物的吸收、分布、代谢和排泄四个过程的差异。     

手性药物的立体选择性药物动力学

手性药物在所有药物中占有相当大的比例,据报道天然或半合成药物几乎都有手性,其中98%以上为单一对映体;全合成药物的40%为手性药物,目前常用的700个药物有一半至少含1个手性中心,但其中90%是以外消旋体形式上市使用的,也就是说目前使用的化学药物很多是药物对映体的混合物.然而手性是生物体系的一个基本特征,很多内源性大分子物质如酶、载体、受体、血浆蛋白和多糖等都具有手性特征,药物与这些生物大分子都是以三维立体形式相互结合并发生作用的.因此立体构型不同的药物进入体内就会产生立体选择性差异,导致药物对映体具有不同的药物动力学过程     

外消旋药物对映体选择性与生物等效性

介绍手性药物对映体选择性,即对映异构体在生物环境中表现出的药物效应和药代动力学性质的特异性,包括药物效应的种类和强度,药物的吸收、分布、代谢、排泄等方面的立体选择性差异。着重讨论可能影响外消旋药物生物等效性评价的对映体选择性,如对映体优劣度差异较大,对映体的主动吸收和转化、非线性药代动力学特征、剂型差异、给药途径、给药速率、首过代谢和特异性蛋白结合等改变优／劣对映体浓度比值。因此,在对映体选择性差     

手性药物的药代动力学立体选择性及其影响因素研究进展

药代动力学立体选择性是指手性药物对映体在吸收、分布、代谢和消除过程中有差异。本文综述了手性药物药代动力学立体选择性及其影响因素方面的最新研究进展。     

唑类抗真菌药物手性分离及药代动力学研究进展

唑类抗真菌药物具有手性特征,给药后体内对映体血药浓度及药动学参数显示出差异,具有立体选择性特点,代谢是导致该类药物呈现立体选择性变化的主要环节。而生物样本中对映体定量分析则依赖于手性拆分技术的不断发展。本文综述了近年来唑类抗真菌药物主要手性分析技术及酮康唑、伊曲康唑手性药代动力学研究进展,以期为唑类抗真菌新药研究提供参考。     

手性药物的药理学立体选择性

人体是一种高度复杂的手性环境，根据立体化学原理，手性药物用于机体后，两对映体与体内的大分子物质结合，形成不同性质的非对映体复合物，呈现作用机制和结合力的差别，从而导致手性药物的体内立体选择性处置特征，产生药理学上的差别。     

手性药物的毒理学特点及安全性评价要点

目前临床上使用的很多药物属于手性药物的消旋体,但手性药物的不同对映体与生物大分子的作用具有不同的选择性,其立体选择性能够对机体产生不同的毒性作用,因此手性药物的安全性评价日益受到重视,各国政府纷纷颁布法规规范手性药物的毒理学评价.通过比较分析不同手性异构体的毒理学作用特点,能够加快研发过程,为临床提供更安全的药物.现综述手性药物独特的毒性作用特点以及不同国家手性药物的安全性评价要点,阐述其毒理学评价基本过程,为手性药物的毒理学评价提供参考.     

HPLC测定体内手性药物的问题及对策

手性药物对映体间存在药理作用差异是近十多年来开始深入研究的。人体生物大分子的有序不对称性使它们能区别对映体，当以外消旋体给药时，两种对映体在体内的吸收、分布、代谢、排泄及与其它药物相互作用可能会完全不同2而体内药动学的立体选择性将直接影响药效和毒副作用的发生等。因此，研宪手性药物。应以立体选择性方法测定生物样品中对映体的浓度，否则仅测定手性药物的总浓度。不仅失去意义，而且可能对合理用药造成错误导向。对映体的拆分测定是一项困难而繁琐的工作，在80年代初开始研究＊＊＊C测定法，目前已取得较大进展，其拆…     

手性药物的立体选择考虑

手性药物的立体选择考虑郭荷民胡季平（安徽医科大学化学教研室，合肥２３００３２）中国图书分类号Ｒ９６２由于生物体内手征性环境的存在，使得手性药物对映体与机体的相互作用存在着立体选择性的差异，传统的手性药物外消旋给药方式所造成的药效滞后及毒副作用等方面的...     

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。     

Chirality and drugs

The two enantiomers of a chiral drug may have vastly different pharmacodynamic and pharmacokinetic properties. As a result, the research and development of chiral drugs raises specific problems some of which are discussed here. Thus, various pharmacokinetic interactions may involve two enantiomers, as seen for example when one enantiomer inhibits the metabolism of the other and modifies its effects. A different situation occurs when a third compound stereoselectively inhibits the metabolism of one of the two enantiomers. Another problem examined here results from the lack of configurational stability of some chiral drugs, a little known phenomenon whose consequences can be of pharmacological or pharmaceutical significance depending on the rate of the reaction of racemization or epimerisation. In-depth investigations are needed before choosing between a eutomer or a racemate.     

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。     

高效毛细管电泳/前沿分析及其在手性药性药物-蛋白结合研究中的应用

目的：综述了高效毛细管电泳／前沿分析（HPCE／FA）方法的原理、特点、及其在手性药物－蛋白结合研究中的应用。方法：采用HPCE／FA方法。结果：不同的手性药物对映体与蛋白结合可能存在判别,同一药物对映体之间与不同蛋白结合率可能存在差别,HPCE／FA仅需极少量样品即可同时测定手性药物各对映体在蛋白结合中的游离浓度。结论：HPCE／FA是一种高效、分析迅速、样本用量极少的研究蛋白结合方法,特别是对于手性药物与昂贵不易获得的蛋白结合研究。     

Do single enantiomers have something special to offer?

Single enantiomers have a significant role to play in enhancing drug discovery and development. Researchers are overcoming the technical limitations associated with developing single enantiomers, and the growth in targeted drug development already means that more single enantiomers are developed ab initio. Moreover, as pharmaceutical companies decide whether to progress a single enantiomer, rather than a racemate, early in development, increasingly fewer racemates will reach the market. Developing a single enantiomer as a line extension of a profitable drug is of growing importance and is reflected in the increasing number of speculative patents on chiral switches. The implications are that single enantiomers will eventually touch every area of clinical medicine. As the number of chiral drugs launched onto the market increases, so clinicians need to be aware of the key issues surrounding enantiomers. This review examines some of the issues arising from the growing importance of enantiomers in medicine. Copyright 2001 John Wiley & Sons, Ltd.     

Bioequivalence of racemic drugs.

Although pharmacokinetic and pharmacodynamic differences between the enantiomers of a chiral drug have been known or suspected for many years, racemate drugs have frequently been developed and approved without clinical pharmacologic consideration of their chiral components. In the late 1970s, the technology to isolate, manufacture, and detect pure enantiomers of racemate drugs became generally available. This availability has created new demands on both pharmaceutical firms and regulatory agencies. To prepare for this new technology, the Center for Drug Evaluation and Research at the Food and Drug Administration is formulating a policy statement to guide evaluation of new chiral drugs. At this time, it appears that whatever new policies are developed will not necessarily be applied retroactively to previously approved racemate drugs. Additional policies to guide the development and approval of generic and OTC chiral drugs may be required. In the Office of Generic Drugs in the Center, abbreviated new drug or antibiotic applications are approved on the basis of adequate chemistry, manufacturing, and control procedures and comparative pharmacokinetics (bioequivalence). The generic drug must be a racemate or single enantiomer if the corresponding innovator drug is a racemate or single enantiomer respectively. Whether a generic firm will be required to provide bioequivalence information on enantiomers of a racemate is determined on a case-by-case basis. Although it might be claimed that a generic drug product should be required only to undergo the same general kind of pharmaceutical evaluation as did the innovator, there may be instances when the approval of a generic drug or antibiotic will require measurement of specific enantiomers of a chiral drug.     

Stereoselective drug disposition: potential for misinterpretation of drug disposition data.

1. Although it is well recognised that the enantiomers of a chiral drug may possess different pharmacokinetic and pharmacodynamic properties, many studies dealing with chiral drugs which are administered as their racemates rely on non-stereoselective analytical techniques. 2. We present a theoretical analysis to illustrate the potential which exists for misinterpretation of drug disposition and plasma drug concentration-effect data generated for a racemic drug using a non-stereoselective assay. 3. It was shown that the use of such an analytical method can lead to the collection of data which may be both quantitatively and qualitatively inaccurate with respect to the individual enantiomers. For example, the clearance of the unresolved drug may indicate concentration- and time-dependence even though this pharmacokinetic process is concentration- and time-independent for each of the enantiomers. 4. The problems discussed emphasise the need to consider stereoselectivity in clinical pharmacological studies involving racemic drugs.     

Investigation of racemisation of the enantiomers of glitazone drug compounds at different pH using chiral HPLC and chiral CE

Drug enantiomers can have biologically distinct interactions within the biological system and consequently different pharmacological or toxicological effects. Development of a better and safer drug product may be considered if one of the enantiomers has a significantly better effect/side effect ratio than the other. Investigation of the single enantiomers in a racemic mixture could be valuable in order to investigate whether the single enantiomers demonstrate difference in pharmacological effect and/or fewer side effects versus the racemic mixture. In this context investigation of a possible racemisation of the pure enantiomers is very important. In order to obtain the enantiomers of the racemic pioglitazone and the racemic rosiglitazone an HPLC method for chiral separation was developed. Using this method the R and S enantiomers were separated and the method was used to collect each enantiomer for investigation of racemisation process. The racemisation of the enantiomers of pioglitazone and rosiglitazone was investigated at pH 2.5, 7.4 and 9.3 using a chiral CE system. At pH 2.5 all enantiomers showed a slow racemisation. After 192 h (8 days) at 37 degrees C the ratio of the enantiomers in the mixture for all four isolated enantiomers was approximately 2 to 1 and after 1440 h (30 days) full racemisation was observed. The racemisation speed increased with increasing pH. At pH 7.4 the ratio of the enantiomers in the mixtures was approximately 2 to 1 already after 10h. Full racemisation was observed within 48 h (2 days) at pH 7.4 and within 24 h at pH 9.3. These investigations have shown that it is possible to separate and isolate the enantiomers from a racemic mixture of glitazone drug substance and perform racemisation studies on each enantiomer.     

Drug disposition in three dimensions: an update on stereoselectivity in pharmacokinetics

Many marketed drugs are chiral and are administered as the racemate, a 50:50 combination of two enantiomers. Pharmacodynamic and pharmacokinetic differences between enantiomers are well documented. Because of enantioselectivity in pharmacokinetics, results of in vitro pharmacodynamic studies involving enantiomers may differ from those in vivo where pharmacokinetic processes will proceed. With respect to pharmacokinetics, disparate plasma concentration vs time curves of enantiomers may result from the pharmacokinetic processes proceeding at different rates for the two enantiomers. At their foundation, pharmacokinetic processes may be enantioselective at the levels of drug absorption, distribution, metabolism and excretion. In some circumstances, one enantiomer can be chemically or biochemically inverted to its antipode in a unidirectional or bidirectional manner. Genetic consideration such as polymorphic drug metabolism and gender, and patient factors such as age, disease state and concomitant drug intake can all play a role in determining the relative plasma concentrations of the enantiomers of a racemic drug. The use of a nonstereoselective assay method for a racemic compound can lead to difficulties in interpretation of data from, for example, bioequivalence or dose/concentration vs effect assessments. In this review data from a number of representative studies involving pharmacokinetics of chiral drugs are presented and discussed.     

ENANTIOSELECTIVE DRUG ANALYSIS: PROBLEMS AND RESOLUTIONS

1. With the increasing appreciation that the enantiomers of a chiral drug can differ pharmacokinetically and/or pharmacodynamically, there is considerable interest in methods for the resolution and quantification of enantiomers. 2. Enantiomers possess identical physical and chemical properties in a symmetrical environment and, therefore, their resolution requires the introduction of an asymmetric or chiral environment allowing diastereomeric interactions. This can be achieved using a number of chromatographic techniques, of which the most developed and widely used is high-performance liquid chromatography (HPLC). 3. Resolution and quantification of enantiomers can be performed using HPLC by either converting the enantiomers to covalent diastereomers prior to chromatography or introducing a chiral environment to the chromatographic system, thereby allowing temporary diastereomeric interactions. 4. Antibodies are chiral molecules which can bind the enantiomers of a chiral drug in a differential manner. This is the basis of enantioselective immunoassay, which is a promising technique for the enantioselective analysis of drugs in biological fluids. 5. Each of the methods available has its limitations, advantages and potential applications in the pharmaceutical industry.