Modeling of Active Transport and Metabolism for Hepatocyte Assays with Application of In Vitro to In Vivo Extrapolation (IVIVE)
Sandwich and suspended hepatocyte cultures are routinely used to assess either active transport and/or metabolism of drug molecules. In vitro assays that evaluate critical drug clearance and metabolism pathways are important in the prediction of hepatobiliary transport, drug-drug interactions, drug induced liver injury (DILI), and the relative importance between active transport and metabolism in hepatocytes. Physiologically based pharmacokinetic (PBPK) models provide quantitative in vivo simulation of drug disposition and drug-drug interactions if Km and Vmax values for the relevant transporters or enzymes can be extracted accurately from in vitro data. To that end, a fully mechanistic simulation of drug transport in both sandwich and suspended hepatocytes was developed in MembranePlus™ (Simulations Plus, Inc.) that allows simultaneous determination of Km and Vmax values for enzymes as well as both influx and efflux transporters. Both models account for additional processes such as drug diffusion through the unstirred boundary layer, sample volume loss, protein binding in both media and cytosol, lysosomal trapping, and drug partitioning into lipid bilayers. Two case studies are presented to demonstrate the applicability of these models. The active uptake and biliary secretion of sodium taurocholate is simulated in the sandwich hepatocyte model. The CYP2D6 metabolism of propafenone is evaluated in the suspended hepatocyte model and, in conjunction with a PBPK model, is used to predict the in vivo exposure.
2017 AAPS Annual Meeting and Exposition, November 12-15, 2017, San Diego, CA
By James Mullin, Viera Lukacova, Walter S. Woltosz, Michael B. Bolger