Investigating Protein-Facilitated Uptake of OATP Substrates: From In Vitro Data to PBPK Modeling
This September, Cyprotex, along with our colleagues at Genentech and Novartis, ran a complimentary webinar series on drug transporters. This blog focuses on the final webinar of the series presented by Christine Bowman PhD of Genentech, entitled ‘Investigating Protein-Facilitated Uptake of OATP Substrates: From In Vitro Data to PBPK Modeling’.
If you missed our other blogs in this series, you can catch up by reading here:
- Read the blog: Part 1, Quantitative Prediction of Drug-Drug Interactions with Common Statin Co-medications
- Read the blog: Part 2, P-gp Transport Kinetics – Compound-specific Selection of In Vitro Assay Design and Kinetic Parameter Estimation
- Read the blog: Part 3, Impact of Pre-Incubation Time on Transporter Inhibition Potency
Membrane transporters such as OATP’s (organic anion transporting polypeptides) play a crucial role in the absorption, distribution, and elimination of drugs. Early in the drug development process it is important to accurately predict drug clearance through the use of in vitro to in vivo extrapolation, though it is not always accurate and can often underpredict in vivo clearance. There are several possibilities why this might be, including not accounting for transporter-mediated hepatic uptake (for instance when using liver microsomes instead of hepatocytes), discrepancies in liver sample preparation and viability, variabilities between donors, not accounting for extra-hepatic metabolism and discrepancies driven by the impact of plasma protein binding.
The impact of plasma protein binding in under predicting the in vivo clearance of low permeability, highly bound, OATP transporter substrates could be explained by a transporter-induced protein binding shift. This theory states that if a highly protein bound drug has a higher affinity for a transporter over that for albumin, then the transporter may be able to strip the drug from the plasma protein thereby enhancing the substrate’s uptake (clearance) into the hepatocyte, rather than it being hindered by its binding to albumin. This phenomenon has significant implications for Km and Vmax determinations for such substrates at the transporter under investigation, which in turn impacts on estimation of intrinsic clearance.
This webinar examines the investigations performed to further define this mechanism for sensitive OATP substrate drugs with a view to provide more accurate hepatic clearance predictions and subsequently more accurate pharmacokinetic (AUC) profile simulations with PBPK modelling.
If you missed out on our webinar series or if you would like the opportunity to watch the webinars again, please click on the links below: