A) Membrane transporters are essential determinants of the ADME, pharmacokinetic and toxicological properties of medicinal products. Membrane Transport (ADE) and Metabolism (ME) are the two main branches of the ADME specificities of drugs. However, as the proportion of BCS Class I and BDDCS Class I molecules is decreasing for molecules currently under development, while the proportion of BCS Class II-IV and BDDCS Class II-VI molecules is increasing (Benet 2011 AAPS J 13:519), the importance of metabolism decreases slightly while membrane transport increases, since the elimination of BCS Class I and BDDCS Class I molecules has been decisively achieved through metabolism. However, this also means that the importance of drug toxicity and adverse reactions through transporter inhibition also increases. In general, the importance of diaphragm transport is significantly increased, as demonstrated by the establishment of the International Transporter Consortium (ITC) to coordinate drug transporter interaction testing and authorisation for pharmaceutical authorities. The ITC’s suggestions show a shift — while the first lita was the material that primarily transports xenobiotics, the recently added transporters have a more balanced profile, i.e. several transporters (Pld. peptide, nucleoside transporters) with important physiological functions (Hillgren 2013 CPT 94:52). Toxicity and adverse reactions are not only about homeostasis on a physiological substrate that is decomposed by inhibition of transporters, but also about drug interactions on transporters. The purpose of this tender is primarily to develop reagents and methods suitable for toxicological applications resulting from the modulation of transporter physiological substrates. At the same time, it also covers, to a lesser extent, relevant drug interactions. This is the next step Solvo needs to take to maintain its position as a market leader. A significant technical aspect of the application is the species specificity test. Appropriate transporters of rat ortology are studied, which are commonly used in preclinical studies. We hope that these studies may partially explain the different toxicity of certain medicinal products in different species. Another important technical aspect of the application is the specificity of each transporter for endogenous substrates. Pharmacokinetic and toxicokinetic modelling now allows small details to be taken into account, and these details are often lacking in the literature. Focusing on organs involved in excretion, liver and kidneys. Here, due to high flu transporter activity, drugs are enriched, which can lead to liver and kidney toxicity, partly through inhibition of transporters. (B)1. Adjusting and validating a test system based on the co-culture of Primer Hepatocytes for endobiotic transport Disturbance of transporters in the liver causes a decrease in bile secretion, cholestasis, resulting in long-term liver damage. One of the most common causes of hepatotoxicity as a drug side effect is cholestasis due to the malfunction of transporters, which required the withdrawal of authorisation for a number of medicinal products (Trauner et al., 2008). The most commonly used animal models in preclinical studies are not sensitive enough to predict hepatotoxicity due to damage to transporters, as evidenced by the large number of molecules undergoing development in late clinical phases due to unexpected toxicity from further development (Morgan et al, 2010). One of the objectives of our tender is to develop complex, primary liver in vitro models, or to receive and validate existing systems (HepatoPac, Hepatocyte-Kuppfer cell co-culture) that are suitable for toxicological testing. These holistic systems should be developed in such a way that all transporters and enzymes specific to their function are properly expressed and thus modelled on a system similar to physiological conditions. As a significant part of the toxic effects does not occur immediately, it is important that the model is functional for an appropriate period of time and that it is maintained throughout the test and that the cellular functions are almost identical. In many publications, it has been described that the development and progression of liver damage is a multi-step process, usually starting with a chemical effect, followed by a biological response of parenchima and non-paraenchima cells. Control mediators emitted by Kupffer cells have a major influence on the activity of hepatocytes, including the expression and activity of transporter proteins. (Tanaka et al. 2006). The sensitivity of individual people to the toxicity of drugs differs. One of the most important mechanistic explanations of idiosyncratic toxicity in the body is often latent infections,