The Forgotten or Underestimated Relevance of Biopharmaceutical-Based Assessments for the Oral Absorption Studies of Oxime Reactivators
The Forgotten or Underestimated Relevance of Biopharmaceutical-Based Assessments for the Oral Absorption Studies of Oxime Reactivators
复制标题
基于生物制药的评估与肟再激活剂口服吸收研究的相关性被遗忘或低估
DOI：
10.1080/17425255.2016.1179282
复制
发表时间：
2016
影响因子：
4.3
通讯作者：
Dalia Simona Miron
中科院分区：
文献类型：
--
作者：
Victor A. Voicu;Andrei Valentin Medvedovici;Koichi Sakurada;Hikoto Ohta;Flavian Stefan Radulescu;Dalia Simona Miron
前言：关于肟类复活剂的吸收、分布、代谢、排泄和毒性(ADME(T))，已根据它们的极性进行了评估，这是它们在有机磷化合物中毒中特殊作用机制的基本要求。治疗结果的局限性不仅与中毒的严重性和毒物的特殊性有关，还与亲脂性降低以及随之而来的限制生物屏障的渗透性有关。内容包括：本文列举了多年来为定义药物具有一个或多个结构和ADME(T)特征的化学空间而制定的过多的运动规则。分析了它们对肟类的适用性，特别是与肠道吸收和脑分布的关系。专家意见：可药剂性规则不适用于肟类复活剂，因为脂类的增加和随之而来的生物屏障渗透性的改善伴随着(神经)毒性的增加和复活能力的降低。现有的数据表明，该化合物具有较高的溶解度和较低的新陈代谢，因此将其归入第四类生物药物分类系统。依赖口服吸收数据来设计安全的中枢作用肟类药物可能具有潜在的价值，并充分描述摄取-内流转运体的相互作用。
Introduction: The absorption, distribution, metabolism, excretion and toxicity (ADME(T)) of oxime reactivators have been assessed with respect to their polarity, a fundamental requirement for their specific mechanism of action in the intoxication with organophosphorous compounds. The limitations of the therapeutic outcome have been associated not only with the severity of intoxication and to particularities of the toxicants, but also to the reduced lipophilicity and consequent restricted permeability across biological barriers.Areas covered: This article inventories the plethora of mnemotic rules developed throughout the years for defining chemical spaces where drugs share one or more structural and ADME(T) characteristics. Their applicability to oxime is analyzed, especially in relation to intestinal absorption and brain distribution. Other aspects of oximes for antidotal outcome are also reviewed.Expert opinion: The drugability rules are not applicable to oxime reactivators, because the increase in lipophicity and consequent improved permeability across biological barrier comes together with amplified (neuro)toxicity and reduced reactivating capacity. The available data suggest a high solubility and reduced metabolism, assigning the quaternary oximes to the fourth class of Biopharmaceutical Classification Systems. Reliance upon oral absorption data for designing safe centrally acting oximes can be of potential value, with adequate characterization of uptake-influx transporters interplay.