CYP reaction phenotyping showed that piperine and SCT are cl

CYP450 reaction phenotyping showed that piperine and SCT-29 are cleared by a single enzyme, CYP1A2 and CYP2C9, respectively, and thus are more sensitive to drug–drug interactions. CYP2C9 contributed significantly in the oxidative metabolism of all analogs. Genetic polymorphism of CYP2C9 may lead to individual variations in drug response [19], [20]. Piperine and all tested analogs exhibited extensive binding to blood constituents, which in turn resulted in a low hepatic extraction ratio calculated for all compounds. The strong protein binding can be explained by the lipophilicity of piperine (cLogP 3.27) and analogs (cLogP 4.70–5.21) [17]. Highly lipophilic compounds tend to bind strongly to plasma proteins, and high lipophilicity also leads to higher metabolic clearance [21].
Conclusions Piperine analogs (SCT-29, LAU 397, and LAU 399) were rapidly metabolized and showed strong binding to blood constituents due to increased lipophilicity. The next cycle of medicinal chemistry optimizations should, therefore, focus on reducing lipophilicity, in order to decrease metabolic liabilities and extensive protein binding [22].
Conflict of interest
Acknowledgements This study was supported by the Swiss National Science Foundation (project 205320_126888, MH). Authors thank Orlando Fertig for technical assistance.
Introduction Corticosteroids are a class of chemicals that includes natural steroid hormones (glucocorticoids and mineralocorticoids), produced from cholesterol in the adrenal BIRB796 of vertebrates, and their synthetic analogues. Fish interrenal glands are capable of secreting adrenocortical steroids. Cortisol has been found in the blood and tissues of several fish species, including rainbow trout (Oncorhynchus mykiss), brown trout (Salmo trutta) (Sloman et al., 2001), and Mozambique tilapia (Oreochromis mossambicus); (Johnstone et al., 2013). Fish kidneys and associated adrenal glands are structured differently than other vertebrates (Perry and Capaldo, 2011). Natural corticosteroids are involved in a broad range of physiological processes (e.g., inflammation) by reducing the response to stress as well as glucose, lipid and protein metabolism. Synthetic equivalents of corticosteroids act in similar ways and can have higher corticosteroid potencird than natural variants (Bentz, 2014). Dexamethasone (DEX), a potent synthetic glucocorticoid drug, is effective for treatment of a range of inflammatory and autoimmune conditions as well as the reduction of side effects associated with chemotherapy. On the Czech Republic pharmaceutical market, DEX is incorporated into eighteen drugs used for treatment of systemic hormonal and sensory organ problems. The Czech Republic was the eighteenth largest EU pharmaceutical market in 2012 (EFPIA, 2013), and its DEX use was 46.13kg in 2013 (SUKL, 2015). In the last few decades, a vast range of synthetic steroid drugs has been produced and released into the aquatic environment where, as a group, they are potential contaminants that disrupt non-target organisms in aquatic environments (Kumar et al., 2015). The concentration of DEX was reportedly 38ngL−1 downstream from a swine farm (Liu et al., 2012). It was reportedly between 1.2 and 23ngL−1 in wastewater influent (Chang et al., 2007, Liu et al., 2011). In river water downstream from a pharmaceutical manufacturing plant discharge, it was 23μgL−1 (Creusot et al., 2014).