MCmB liver model for drug metabolism prediction

We have developed a “system on a plate” modular multicompartmental bioreactor (MCmB) array which enables microwell protocols to be transferred directly to the bioreactor modules, without redesign of cell culture experiments. It is currently commercialized by Kirkstall Ltd, under the tradename Quasi-Vivo TM. The new system offers mechanical stimuli from flow and biochemical stimuli from cells placed in connected modules, and can be used for assessing the human hepatotoxicity potential of drugs, or for pharmacological or pharmacokinetic studies. Human hepatocytes were cultured in the MCmB system and subject to various flow rates for up to 7 days. Both gene expression and drug metabolism were quantified with respect to freshly isolated hepatocytes from the same liver sample, as well as cells in control (multiwell) conditions. The results show that most relevant CYP450 in drug metabolism (CYP 3A4, 2B6, 1A2, 1A1) are upregulated at mRNA level analysis in the MCmB device, in several cases approximating levels of expression in freshly isolated hepatocytes. This upregulation is confirmed by analysis in HPLC MS/MS of drug metabolism specific activities (Midazolam substrate for CYP3A4, Phenacetin for CYP1A2). The MCmB system thus recreates conditions more similar to the physiological environment.