Diabetes is one of the World's most concerning health problems and millions of patients are using anti-diabetic drugs (ADDs) in order to control blood glucose. The in vitro H295R steroidogenesis assay was implemented to investigate endocrine effects of three ADDs, metformin (MET), glimepiride (GLIM), sitagliptin (SIT) and the cholesterol-lowering drug simvastatin (SIM) individually and in three binary mixtures. Steroid hormones were analyzed using LC-MS/MS. Mixture effects were assessed by applying the Concentration Addition (CA) model. All tested drugs and binary mixtures interrupted the H295R steroidogenesis with different potency. The effects of MET:GLIM on the steroidogenesis were overall similar to the steroidogenic profile of GLIM, however effects were less pronounced. The binary mixture of MET:SIT showed overall minor effects on steroid production and only at very high concentrations. The SIM:SIT mixture showed inhibition downstream from cholesterol, which was attributed to the effects of SIM. The CA model partly predicted the effect of MET:SIT on some steroids but significantly overestimated the effects of MET:GLIM and SIM:SIT. Thus, the applicability of the CA model was limited and cocktail effects appeared to be intermediate responses of individual drugs, rather than additive. The complexity of dynamic pathways such as steroidogenesis appears to significantly reduce the use of the CA model. In conclusion, more dynamic models are needed to predict mixture effects in complex systems.

糖尿病是世界上最令人担忧的健康问题之一，数以百万计的患者正在使用抗糖尿病药物 (ADD) 来控制血糖。实施体外 H295R 类固醇生成测定以研究三种 ADD，二甲双胍 (MET)、格列美脲 (GLIM)、西他列汀 (SIT) 和降胆固醇药物辛伐他汀 (SIM) 单独和在三种二元混合物中的内分泌作用。使用 LC-MS/MS 分析类固醇激素。通过应用浓度加成 (CA) 模型评估混合效应。所有测试的药物和二元混合物都以不同的效力中断了 H295R 类固醇生成。MET:GLIM 对类固醇生成的影响总体上与 GLIM 的类固醇生成谱相似，但影响不太明显。MET的二元混合物：SIT 对类固醇产生的总体影响很小，并且仅在非常高的浓度下。SIM:SIT 混合物显示出胆固醇下游的抑制作用，这归因于 SIM 的影响。CA 模型部分预测了 MET:SIT 对某些类固醇的影响，但显着高估了 MET:GLIM 和 SIM:SIT 的影响。因此，CA 模型的适用性是有限的，鸡尾酒效应似乎是单个药物的中间反应，而不是叠加。类固醇生成等动态途径的复杂性似乎显着减少了 CA 模型的使用。总之，需要更多的动态模型来预测复杂系统中的混合效应。这归因于SIM的影响。CA 模型部分预测了 MET:SIT 对某些类固醇的影响，但显着高估了 MET:GLIM 和 SIM:SIT 的影响。因此，CA 模型的适用性是有限的，鸡尾酒效应似乎是单个药物的中间反应，而不是叠加。类固醇生成等动态途径的复杂性似乎显着减少了 CA 模型的使用。总之，需要更多的动态模型来预测复杂系统中的混合效应。这归因于SIM的影响。CA 模型部分预测了 MET:SIT 对某些类固醇的影响，但显着高估了 MET:GLIM 和 SIM:SIT 的影响。因此，CA 模型的适用性是有限的，鸡尾酒效应似乎是单个药物的中间反应，而不是叠加。类固醇生成等动态途径的复杂性似乎显着减少了 CA 模型的使用。总之，需要更多的动态模型来预测复杂系统中的混合效应。类固醇生成等动态途径的复杂性似乎显着减少了 CA 模型的使用。总之，需要更多的动态模型来预测复杂系统中的混合效应。类固醇生成等动态途径的复杂性似乎显着减少了 CA 模型的使用。总之，需要更多的动态模型来预测复杂系统中的混合效应。