Fraunhofer Institute for Molecular Biology and Applied Ecology, Branch for Translational Medicine and Pharmacology, Theodor-Stern-Kai 7, 60596, Frankfurt am Main, Germany; Institute of Pharmaceutical Technology, Goethe University, Max-von-Laue-Straße 9, 60438, Frankfurt, Main, Germany.
Fraunhofer Institute for Molecular Biology and Applied Ecology, Branch for Translational Medicine and Pharmacology, Theodor-Stern-Kai 7, 60596, Frankfurt am Main, Germany.
Environ Res. 2021 Jan;192:110219. doi: 10.1016/j.envres.2020.110219. Epub 2020 Sep 24.
Today, environmental pollution with pharmaceutical drugs and their metabolites poses a major threat to the aquatic ecosystems. Active substances such as fenofibrate, are processed to pharmaceutical drug formulations before they are degraded by the human body and released into the wastewater. Compared to the conventional product Lipidil® 200, the pharmaceutical product Lipidil 145 One® and Ecocaps take advantage of nanotechnology to improve uptake and bioavailability of the drug in humans. In the present approach, a combination of in vitro drug release studies and physiologically-based biopharmaceutics modeling was applied to calculate the emission of three formulations of fenofibrate (Lipidil® 200, Lipidil 145 One®, Ecocaps) into the environment. Special attention was paid to the metabolized and non-metabolized fractions and their individual toxicity, as well as to the emission of nanomaterials. The fish embryo toxicity test revealed a lower aquatic toxicity for the metabolite fenofibric acid and therefore an improved toxicity profile. When using the microparticle formulation Lipidil® 200, an amount of 126 mg of non-metabolized fenofibrate was emitted to the environment. Less than 0.05% of the particles were in the lower nanosize range. For the nanotechnology-related product Lipidil 145 One®, the total drug emission was reduced by 27.5% with a nanomaterial fraction of approximately 0.5%. In comparison, the formulation prototype Ecocaps reduced the emission of fenofibrate by 42.5% without any nanomaterials entering the environment. In a streamlined life cycle assessment, the lowered dose in combination with a lowered drug-to-metabolite ratio observed for Ecocaps led to a reduction of the full life cycle impacts of fenofibrate with a reduction of 18% reduction in the global warming potential, 61% in ecotoxicity, and 15% in human toxicity. The integrated environmental assessment framework highlights the outstanding potential of advanced modeling technologies to determine environmental impacts of pharmaceuticals during early drug development using preclinical in vitro data.
如今，药物及其代谢物对水生生态系统造成了严重的环境污染威胁。芬诺贝特等活性物质在被人体代谢并排入废水之前，会被加工成药物制剂。与传统产品 Lipidil® 200 相比，药物产品 Lipidil 145 One® 和 Ecocaps 利用纳米技术提高了药物在人体内的吸收和生物利用度。在本研究中，采用体外药物释放研究和基于生理的生物药剂学模型相结合的方法，计算了三种芬诺贝特制剂（Lipidil® 200、Lipidil 145 One®、Ecocaps）进入环境的排放情况。特别关注了代谢和非代谢部分及其各自的毒性，以及纳米材料的排放。鱼类胚胎毒性试验表明，代谢产物非诺贝特酸的水生毒性较低，因此毒性特征得到改善。使用微粒制剂 Lipidil® 200 时，有 126 毫克未代谢的芬诺贝特排放到环境中。不到 0.05%的颗粒处于较小的纳米尺寸范围内。对于与纳米技术相关的产品 Lipidil 145 One®，总药物排放量减少了 27.5%，纳米材料部分约为 0.5%。相比之下，制剂原型 Ecocaps 减少了 42.5%的芬诺贝特排放，而没有任何纳米材料进入环境。在简化的生命周期评估中，Ecocaps 观察到的剂量降低和药物-代谢物比率降低，导致芬诺贝特的全生命周期影响降低，全球变暖潜力降低了 18%，生态毒性降低了 61%，人类毒性降低了 15%。综合环境评估框架突出了先进建模技术的卓越潜力，可利用临床前体外数据在药物早期开发阶段确定药物对环境的影响。
