In vitro models for hepatic drug handling and drug-induced cholestasis
Tuesday 25th June, 2017 – Pieter Annaert & the hepatic drug disposition group at the KU Leuven
The hepatic drug disposition group at the KU Leuven Drug Delivery and Disposition Lab has many years of experience in the development and application of in vitro models for hepatic drug handling and drug-induced cholestasis. In addition, the group has bioanalytical expertise in LC-MS/MS, as well as growing experience in Physiologically-based Pharmacokinetic (PBPK) modelling.
In particular, our group is routinely using the ‘oil-spin method’ to quantify transporter-mediated uptake and sinusoidal efflux of xenobiotics in suspended hepatocytes. Moreover, for determination of biliary excretion of drugs and their metabolites, sandwich-cultured hepatocytes are used. On the other hand, drug metabolism is typically measured in liver microsomes or suspended hepatocytes.
In Vitro-In Vivo Extrapolation (IVIVE) approaches are subsequently used to convert the obtained in vitro disposition data to the in vivo context and units. These scaled disposition data are implemented in PBPK models to predict in vivo drug exposure and behaviour. For instance, our group has succesfully predicted in vivo clearance of the various HIV protease inhibitors based on in vitro hepatic disposition measurements in microsomes, suspended hepatocytes and transporter-transfected cells. Currently, we are applying cellular compartmental modelling to better understand hepatic disposition processes.
Our group has experience with several modelling platforms, including Simcyp®, NONMEM®, Berkeley-Madonna and R / PMetrics. To support in vitro experiments, plateable animal hepatocytes are isolated and cryopreserved in-house, while cryopreserved human hepatocytes are obtained via strategic collaborations.
We are keen to share with you our expertise in these domains by a program balancing theoretical background with hands-on sessions.