Abstract

Previously we undertook studies to assess the inductive response of prototypical inducers in hepatocyte monocultures and the long term co-culture model, HepatoPac™, using hepatocytes from the same donors (Dixit et al., 2016). We noted that the rifampicin EC50 generated using the HepatoPac model corresponded better to the EC50 based upon clinical data compared to data generated in the monoculture system. We postulated that there may be differences in the functioning of uptake transporters between the two systems which may have led to the EC50 difference. In this study, we characterized the functional activity of multiple uptake transporters in the two systems using hepatocytes from the same donors. Our data suggests that uptake transporter activity is higher in HepatoPac compared to the monoculture system. As a follow-up to this study, we measured the intracellular concentrations of rifampicin and bosentan which are known substrates of uptake transporters and observed significantly higher intracellular concentrations of both compounds in HepatoPac relative to the monoculture system. This finding equated to lower CYP3A4 EC50 values in the HepatoPac system compared to the monoculture system for both mRNA and activity. In parallel, no significant EC50 shift was observed for carbamazepine and phenytoin which are not known to be substrates of uptake transporters. Our data suggests that next generation liver models, like HepatoPac, may be a useful in vitro tool to quantitatively predict DDIs when it is known that the perpetrator is also a substrate of drug transporters.