Drug chirality: impact on pharmaceutical regulation.
Drug chirality: impact on pharmaceutical regulation.
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作者：
A. Hutt
IBC法律的研究和服务有限公司的法规事务部最近（1990年10月）在伦敦新闻中心组织了一次为期两天的研讨会，主题如上，目的是总结药物手性的基础科学及其对药物开发和法规的意义。研讨会吸引了大约200名代表，主要是欧洲人，但也有来自美国、日本和南非的代表，反映出人们对药物分子立体化学领域的兴趣日益浓厚。会议第一天由Anthony Cartwright（伦敦）主持，开幕式上AF Fell教授（布拉德福德）介绍了手性分析的方法。Fell首先介绍了药理学中立体化学考虑的重要性，并评论说，目前对这一领域的兴趣是由于最近药物对映体分析测定技术的快速发展。报告的大部分内容涉及对液相色谱可用手性固定相（CSP）的讨论（目前约有50种），并指出，除了Pirkle和环糊精CSP外，给定分析的色谱柱选择仍然非常依赖于直观方法。结合手性药物的对映体拆分，说明了手性药物生物分析的困难，手性药物的两种主要代谢产物的对映体不能使用相同的系统进行拆分。Fell还讨论了作为对映体拆分辅助手段的各种优化方法，并展示了使用β-环糊精CSP获得的一些令人印象深刻的结果，在进行了大量初步实验后，他能够以非常高的准确度预测分析物保留和拆分值。上午的第二个演讲是EJ Ariens教授（奈梅亨）的典型挑战性演讲。Ariens首先就药理学和毒理学领域的一些标准教科书和期刊发表了一些关于立体化学意识或缺乏立体化学意识的评论，并将缺乏相关信息描述为立体恐惧症。其次是考虑药物手性的程度，在制药市场上，大多数合成手性药物作为外消旋体而不是纯对映体销售。
The Regulatory Affairs Division of IBC Legal Studies and Services Limited recently (October, 1990) organised a 2-day seminar, with the above title, at the London Press Centre with the object of providing a summary of the basic science underlying drug chirality and its significance on pharmaceutical development and regulation. The seminar attracted an audience of some 200 delegates, predominantly European but with representation from the United States, Japan, and South Africa, reflecting the ever increasing interest in the area of the stereochemistry of drug molecules. The first day of the meeting was chaired by Anthony Cartwright (London) and opened with a presentation on the methodological aspects of chiral analysis by Professor AF Fell (Bradford). Fell began his presentation with some introductory remarks concerning the significance of stereochemical considerations in pharmacology and made the comment that the current interest in this area has been due to the recent rapid developments in the technology available for the analytical determination of drug enantiomers. The majority of the presentation involved a discussion of the chiral stationary phases (CSPs) available for liquid chromatography (ca 50 being currently available), and it was pointed out that apart from the Pirkle and cyclodextrin CSPs, column selection for a given analysis still relies very much on an intuitive approach. The difficulties associated with chiral drug bioanalysis were illustrated with reference to the enantiomeric resolution of a chiral drug, the enantiomers of the two major metabolites of which could not be resolved using the same system. Fell also discussed various optimization methods as an aid for enantiomeric resolution and presented some impressive results obtained with a p-cyclodextrin CSP with which, following a number of preliminary experiments, he was able to predict both analyte retention and resolution values with a remarkable degree of accuracy.The second presentation of the morning was a typically challenging talk by Professor EJ Ariens (Nijmegen). Ariens opened with some comments concerning stereochemical awareness-or lack of itwith respect to several standard texts and journals in the areas of pharmacology and toxicology, describing the lack of relevant information as a stereophobia. This was followed by a consideration of the extent of drug chirality in terms of the pharmaceutical market place with the majority of synthetic chiral agents being marketed as racemates rather than as pure enantiomers.