In vitro systems are used extensively in the drug discovery and drug development process. Drugs are taken up into the hepatocytes through passive diffusion and/or active uptake by transport proteins present on the basolateral membrane of the hepatocytes. Once inside the hepatocyte, drugs may undergo metabolism, and the drug and/or generated metabolites may be effluxed across the canalicular membrane into the bile or across the basolateral membrane into the systemic circulation. In this study, mechanistic pharmacokinetic (PK) modeling of data obtained from sandwich-cultured human hepatocytes using B-CLEAR® technology was used to characterize the functional changes in bile acid transporters that occur with FXR activation, the primary regulatory pathway for bile acids. The effects of two FXR agonists on the hepatobiliary disposition of a model bile acid revealed dramatic changes in the hepatobiliary disposition of bile acids due to increases in both the basolateral efflux clearance and biliary efflux clearance which were consistent with a pronounced upregulation of OSTα/β protein expression and a smaller increase in BSEP protein expression. This study demonstrated the advantages of PK modeling in assessing changes in concurrent clearance pathways in a whole cell system.
