The goal of minimising dose, prolonging half-life, and improving exposure of drugs is driving the increased prevalence of low clearance compounds in drug discovery portfolios. However, accurate assessment of low clearance compounds is a particular challenge within drug discovery. Short term metabolism studies in microsomes or hepatocyte suspensions are limited by assay sensitivity for low clearance compounds, resulting in a large variability in estimated intrinsic clearance (CLint). This can, in turn, lead to uncertainty in the in vivo human clearance prediction and, ultimately, the ability to achieve the desired exposure in the clinic.
Plated monolayer cultures of cryopreserved human hepatocytes have been proposed as more suitable models for the accurate CLint determination of low clearance compounds by allowing for longer incubation times; modifications to standard 2D cell culture systems assist in ensuring enzymatic activity for number of days, if not weeks. HµREL® provide a co-culture of primary human hepatocytes plus non-parenchymal stromal-type cells, which have been specifically designed to maintain cellular function for use in such long-term cell culture.
We have demonstrated the effective use of the HµREL® human hepatocyte co-culture model in determining the CLint for slowly metabolised compounds, as well as its suitability for metabolite formation studies due to the longevity of the co-culture. This validation has been presented at the ISSX 2019 conference by our Head of ADME, Dr. Phil Butler. To find out more: