Fraunhofer Institute for Molecular Biology and Applied Ecology IME, Theodor-Stern-Kai 7, 60596, Frankfurt/Main, Germany; Fraunhofer Institute for Molecular Biology and Applied Ecology IME, Auf dem Aberg 1, 57392, Schmallenberg, Germany; Goethe University Frankfurt am Main, Department Aquatic Ecotoxicology, Max-von-Laue-Str. 13, 60438, Frankfurt am Main, Germany.
Fraunhofer Institute for Molecular Biology and Applied Ecology IME, Auf dem Aberg 1, 57392, Schmallenberg, Germany.
Aquat Toxicol. 2021 May;234:105798. doi: 10.1016/j.aquatox.2021.105798. Epub 2021 Mar 8.
A wide variety of active pharmaceutical ingredients are released into the environment and pose a threat to aquatic organisms. Drug products using micro- and nanoparticle technology can lower these emissions into the environment by their increased bioavailability to the human patients. However, due to this enhanced efficacy, micro- and nanoscale drug delivery systems can potentially display an even higher toxicity, and thus also pose a risk to non-target organisms. Fenofibrate is a lipid-regulating agent and exhibits species-related hazards in fish. The ecotoxic effects of a fenofibrate formulation embedded into a hydroxypropyl methylcellulose microparticle matrix, as well as those of the excipients used in the formulation process, were evaluated. To compare the effects of fenofibrate without a formulation, fenofibrate was dispersed in diluted ISO water alone or dissolved in the solvent DMF and then added to diluted ISO water. The effects of these various treatments were assessed using the fish embryo toxicity test, acridine orange staining and gene expression analysis assessed by quantitative RT polymerase chain reaction. Exposure concentrations were assessed by chemical analysis. The effect threshold concentrations of fenofibrate microparticle precipitates were higher compared to the formulation. Fenofibrate dispersed in 20%-ISO-water displayed the lowest toxicity. For the fenofibrate formulation as well as for fenofibrate added as a DMF solution, greater ecotoxic effects were observed in the zebrafish embryos. The chemical analysis of the solutions revealed that more fenofibrate was present in the samples with the fenofibrate formulation as well as fenofibrate added as a DMF solution compared to fenofibrate dispersed in diluted ISO water. This could explain the higher ecotoxicity. The toxic effects on the zebrafish embryo thus suggested that the formulation as well as the solvent increased the bioavailability of fenofibrate.
大量的活性药物成分被释放到环境中，对水生生物构成威胁。采用微纳米技术的药物产品可以通过提高对人类患者的生物利用度来降低这些向环境中的排放。然而，由于这种增强的功效，微纳米药物递送系统可能表现出更高的毒性，因此也对非目标生物构成风险。非诺贝特是一种调节脂质的药物，在鱼类中表现出种属相关的危害。评估了嵌入羟丙基甲基纤维素微颗粒基质中的非诺贝特制剂以及制剂过程中使用的赋形剂的生态毒性效应。为了比较没有制剂的非诺贝特的影响，将非诺贝特单独分散在稀释的 ISO 水中或溶解在溶剂 DMF 中，然后添加到稀释的 ISO 水中。使用鱼类胚胎毒性试验、吖啶橙染色和定量 RT-PCR 基因表达分析评估这些不同处理的影响。通过化学分析评估暴露浓度。与制剂相比，非诺贝特微颗粒沉淀物的效应阈值浓度更高。分散在 20%-ISO 水中的非诺贝特显示出最低的毒性。对于非诺贝特制剂以及作为 DMF 溶液添加的非诺贝特，在斑马鱼胚胎中观察到更大的生态毒性效应。对溶液的化学分析表明，与分散在稀释的 ISO 水中的非诺贝特相比，含有非诺贝特制剂和非诺贝特作为 DMF 溶液添加的样品中存在更多的非诺贝特。这可以解释更高的生态毒性。因此，对斑马鱼胚胎的毒性作用表明制剂和溶剂增加了非诺贝特的生物利用度。
