The successful combination of high-throughput screening, metabolite identification and creative design can generate compounds for which the metabolism is difficult to detect and/or quantify in traditional systems. Furthermore, acidic compounds often require remarkably low clearance estimates in order to provide a satisfactory pharmacokinetic half-life. Predicting the clearance of such compounds is a common challenge in drug discovery and development. Routine in vitro metabolic clearance assays using either microsomes or hepatocytes in suspension have certain limitations, and prolonging the incubation time typically impairs enzymatic activity and/or reduces cell viability.
So how are these problems overcome? Maintaining the enzymatic activity is the key. In a recent poster presented at ISSX in Rhode Island in September 2017, Cyprotex’s parent company Evotec demonstrated the accurate prediction of human hepatic clearance using an overlay approach (Geltrex®) coupled with proprietary media (HepExtendTM) developed by Thermo Scientific. Over a 5 day period, it was shown that enzymatic activity and mRNA levels as well as cell viability were maintained and the system was able to predict human hepatic clearance within 2-fold for 80% of compounds tested for three human donors with an average fold error of 2.2.
To find out more about the research, read the poster