Islam M R, Mahdi J G, Bowen I D
School of Pure and Applied Biology, University of Wales College of Cardiff, UK.
Drug Saf. 1997 Sep;17(3):149-65. doi: 10.2165/00002018-199717030-00002.
Drug enantiomers have identical properties in an achiral environment, but should be considered as different chemical compounds. This is because they often differ considerably in potency, pharmacological activity and pharmacokinetic profile, since the modules with which they interact in biological systems are also optically active. Within biological systems, the metabolism of one isomer may be via a different pathway or occur at a different rate from that of the other isomer. Preferential binding of one isomer to plasma proteins may cause differences in circulating free drug and hence alter concentrations at active sites. Interactions of both isomers may differ at the active sites through which pharmacological action is mediated. Actions and levels of activity of the stereoisomers in vivo may also differ. All the pharmacological activity may reside in a single enantiomer, whereas several possibilities exist for the other enantiomer-- it may be inactive, have a qualitatively different effect, an antagonistic effect or produce greater toxicity. Two isomers may have nearly identical qualitative pharmacological activity, qualitatively similar pharmacological activity but quantitatively different potency, or qualitatively different pharmacological activity. To avoid adverse effects and optimise the therapeutic value of enantiomeric drugs, it is necessary that methods for the resolution of racemates be evolved and devolved to determine isomeric purity, establish the effectiveness of isomers of the drug, and detect the presence of an enantiomer with lower therapeutic activity and undesirable adverse effects. Even if a drug is given as a pure enantiomer, methods to discriminate between enantiomers are required because racemisation can occur both in vitro and in vivo. Methods developed for resolution of drug enantiomers should facilitate routine testing of single isomers and their metabolites, studies of pharmacological, toxicological and clinical effectiveness, routine analysis of racemates, pure enantiomers or intermediates in manufacturing processes, and investigation of the potential for inversion of an enantiopure drug substance during the early stages of drug development and therapeutic drug monitoring.
药物对映体在手性环境中具有相同的性质，但应被视为不同的化合物。这是因为它们在效力、药理活性和药代动力学特征方面往往有很大差异，因为它们在生物系统中相互作用的模块也是光学活性的。在生物系统中，一种异构体的代谢可能通过不同的途径进行，或者其代谢速率与另一种异构体不同。一种异构体与血浆蛋白的优先结合可能导致循环中游离药物的差异，从而改变活性部位的浓度。两种异构体在介导药理作用的活性部位的相互作用也可能不同。体内立体异构体的作用和活性水平也可能不同。所有的药理活性可能都存在于单一的对映体中，而另一种对映体则有几种可能性——它可能无活性、具有性质不同的作用、拮抗作用或产生更大的毒性。两种异构体可能具有几乎相同的定性药理活性、定性相似但定量效力不同的药理活性，或定性不同的药理活性。为了避免不良反应并优化对映体药物的治疗价值，有必要开发和改进外消旋体拆分方法，以确定异构体纯度、确定药物异构体的有效性，并检测具有较低治疗活性和不良副作用的对映体的存在。即使药物以纯对映体形式给药，也需要区分对映体的方法，因为外消旋化可能在体外和体内发生。为拆分药物对映体而开发的方法应便于对单一异构体及其代谢物进行常规检测、药理、毒理和临床有效性研究、外消旋体、纯对映体或制造过程中的中间体的常规分析，以及在药物开发早期和治疗药物监测期间对对映体纯药物物质的转化可能性进行研究。
