Mixture toxicity of the antiviral drug Tamiflu® (oseltamivir ethylester) and its active metabolite oseltamivir acid
Mixture toxicity of the antiviral drug Tamiflu® (oseltamivir ethylester) and its active metabolite oseltamivir acid
复制标题
DOI：
10.1016/j.aquatox.2009.10.020
复制
发表时间：
2010-02-18
影响因子：
4.5
通讯作者：
Straub, Juerg Oliver
中科院分区：
文献类型：
--
作者：
Escher, Beate I.;Bramaz, Nadine;Straub, Juerg Oliver
达菲（R）（奥司他韦乙酯）是一种用于治疗甲型和B型流感的抗病毒剂。前体药物达菲（R）在人体内转化为抗病毒活性代谢物奥司他韦酸，产率为75%。奥司他韦酸在污水处理厂和沉积物/水系统中是间接光降解和缓慢生物降解的。先前的一项环境风险评估得出结论，这两种化合物均无生物累积潜力。然而，对代谢物的生态毒性知之甚少。酯水解通常降低化合物的疏水性，从而降低化合物的毒性。在这种情况下，由带电母体化合物形成两性离子但总体中性的物质。如果考虑到形态形成和预测的生物膜分配，代谢物可能对总体毒性有相关贡献。这些理论上的考虑引发了一项研究，以调查奥司他韦酸（OA），单独和二元混合物与其母体化合物奥司他韦乙酯（OE）的毒性。OE和OA被发现是基线毒物的生物发光抑制试验与费氏弧菌。他们的混合物效应之间的预测浓度增加和独立行动的混合物比例排泄在尿液和9个额外的混合物比例的OE和OA。与此相反，OE是一个数量级的毒性比OA对藻类，具有更明显的效果时，直接抑制光系统II被用作毒性终点，而不是24小时的生长速率终点。该试验中的二元混合物产生的实验混合物效应与独立作用的预测一致。这与OE表现出轻微增强的毒性，而OA作为基线毒物的发现一致。因此，就混合物分类而言，这两种化合物可被视为根据不同的毒性作用模式起作用，尽管有迹象表明，这种差异是毒代动力学效应，而不是毒性机制的真正差异。一般混合物的结果说明，需要考虑药物的风险评估中代谢物的作用。然而，在母体药物与人体排泄代谢物的浓度比中，实验结果证实活性代谢物对混合物的风险商数没有显著影响。(C)2009 Elsevier B. V.保留所有权利。
Tamiflu (R) (oseltamivir ethylester) is an antiviral agent for the treatment of influenza A and B. The prodrug Tamiflu (R) is converted in the human body to the pharmacologically active metabolite, oseltamivir acid, with a yield of 75%. Oseltamivir acid is indirectly photodegradable and slowly biodegradable in sewage works and sediment/water systems. A previous environmental risk assessment has concluded that there is no bioaccumulation potential of either of the compounds. However, little was known about the ecotoxicity of the metabolite. Ester hydrolysis typically reduces the hydrophobicity and thus the toxicity of a compound. In this case, a zwitterionic, but overall neutral species is formed from the charged parent compound. If the speciation and predicted partitioning into biological membranes is considered, the metabolite may have a relevant contribution to the overall toxicity. These theoretical considerations triggered a study to investigate the toxicity of oseltamivir acid (OA), alone and in binary mixtures with its parent compound oseltamivir ethylester (OE). OE and OA were found to be baseline toxicants in the bioluminescence inhibition test with Vibrio fischeri. Their mixture effect lay between predictions for concentration addition and independent action for the mixture ratio excreted in urine and nine additional mixture ratios of OE and OA. In contrast, OE was an order of magnitude more toxic than OA towards algae, with a more pronounced effect when the direct inhibition of photosystem II was used as toxicity endpoint opposed to the 24 h growth rate endpoint. The binary mixtures in this assay yielded experimental mixture effects that agreed with predictions for independent action. This is consistent with the finding that OE exhibits slightly enhanced toxicity, while OA acts as baseline toxicant. Therefore, with respect to mixture classification, the two compounds can be considered as acting according to different modes of toxic action, although there are indications that the difference is a toxicokinetic effect, not a true difference of mechanism of toxicity. The general mixture results illustrate the need to consider the role of metabolites in the risk assessment of pharmaceuticals. However, in the concentration ratio of parent to metabolite excreted by humans, the experimental results confirm that the active metabolite does not significantly contribute to the risk quotient of the mixture. (C) 2009 Elsevier B.V. All rights reserved.