Senior Principle Scientist Merck & Co., Inc. Rahway, New Jersey
OATP1B1 and OATP1B3 are major human hepatic uptake transporters that play important roles in the disposition and elimination of many clinically important drugs, such as statins. OATP1B-related victim pharmacokinetic drug -drug interaction studies are recommended by regulatory agencies if OATP1B-mediated hepatic uptake is one of major contributors to the elimination of the NME. Currently, in vitro assays are routinely used to identify OATP1B substrates and in vitro transporter kinetic studies have been explored to predict pharmacokinetics of OATP1B substrate drugs in human using in vitro to in vivo extrapolation (IVIVE) approach. However, in vitro assays have the limitations to study the compounds with poor solubility and/or high nonspecific binding, and generally have low confidence in IVIVE. Oatp1a/1b knockout and OATP1B1 and -1B3 humanized rodent models therefore have been developed and can be useful as emerging tools to bridge such translational gaps to understand in vivo function of human OATP1B early in drug discovery.
This presentation aims to 1) provide a comprehensive characterization of humanized OATP1B1 and -1B3 rats, 2) discuss case studies of applying knockout/humanized OATP1B rats to study in vivo roles of OATP1B in drug disposition, and 3) provide an industry perspective on the application and limitations of humanized rodent models to study OATP1B-mediated disposition is drug discovery.
Understand the advantages and limitations of applying humanized OATP1B rodent models to study OATP1B function
Learn how to design the studies and interpret in vivo data generated in Oatp1a/1b knockout/OATP1B humanized rodent models
Learn how to apply humanized rodent models to study in vivo relevance of OATP1B in drug discovery