Srinivas Nuggehally R
Global Drug Development, ClinTec (India) International Pvt Ltd, 3rd Floor, 'A' Wing, Divyasree Chambers, Langford Road, Bangalore 560 025, India.
Curr Clin Pharmacol. 2009 Jan;4(1):67-70. doi: 10.2174/157488409787236065.
The field of chemoprevention continues to be a heavily researched area since a few decades now. Whereas, the dietary intake of flavonoids occur via daily intakes of fruits, vegetables, herbal preparations, beverages etc, it appears that the active ingredients(s) contained in these dietary sources may not reach the required plasma and/or tissue concentrations in vivo to produce the desired pharmacological response expected of these agents. Akin to the common problems of druggability encountered often times in drug discovery/development scenario, low bioavailability of flavonoids have been attributed to: lack of stability, excessive metabolism, permeability problems, lack of site specificity in distribution, rapid elimination etc. The scope of the review is to assess and put into perspectives salient features of some of the recently reported work on dietary flavonoids including the methylated compounds that showed improved drug-like properties in context with the required features for the lead optimization program rendering a clinical candidate. In addition, it aims to provide some perspectives into the present day considerations for early drug development such as healthy subjects versus cancer patients, single agent versus combination potential with other cancer therapeutics, selection of a cancer indication, potential for drug-drug interaction etc. Although there has been an unabated use of 'dietary flavonoids' with tall order claims for chemoprevention, it may be extremely challenging to confirm it in a clinical setting. Overall, it appears prudent to develop a comprehensive prospective strategy for clinical development and regulatory approval.
几十年来，化学预防领域一直是一个研究热点。尽管黄酮类化合物可通过日常摄入水果、蔬菜、草药制剂、饮料等进入饮食，但这些饮食来源中所含的活性成分在体内可能无法达到产生这些药物预期药理反应所需的血浆和/或组织浓度。与药物发现/开发过程中经常遇到的成药常见问题类似，黄酮类化合物的低生物利用度归因于：缺乏稳定性、过度代谢、通透性问题、分布缺乏位点特异性、快速消除等。本综述的范围是评估并审视一些最近报道的关于膳食黄酮类化合物的重要研究成果，包括甲基化化合物，这些化合物在与先导优化计划所需特征相关的方面表现出改善的类药性质，从而成为临床候选药物。此外，它旨在为早期药物开发的当前考量提供一些观点，例如健康受试者与癌症患者、单药与与其他癌症治疗药物联合使用的潜力、癌症适应症的选择、药物相互作用的可能性等。尽管“膳食黄酮类化合物”一直被大量用于化学预防的高要求声明中，但在临床环境中证实这一点可能极具挑战性。总体而言，制定一个全面的临床开发和监管批准前瞻性策略似乎是审慎的做法。
