We have located links that may give you full text access.
Journal Article
Research Support, Non-U.S. Gov't
Prediction and Quantification of Hepatic Transporter-Mediated Uptake of Pitavastatin Utilizing a Combination of the Relative Activity Factor Approach and Mechanistic Modeling.
Quantification of the fraction transported (ft ) by a particular transporter will facilitate more robust estimations of transporter interactions. Using pitavastatin as a model uptake transporter substrate, we investigated the utility of the relative activity factor (RAF) approach and mechanistic modeling to estimate ft in hepatocytes. The transporters evaluated were organic anion-transporting polypeptides OATP1B1 and OATP1B3 and sodium-taurocholate cotransporting polypeptide. Transporter-expressing human embryonic kidney 293 cells and human hepatocytes were used for determining RAF values, which were then incorporated into the mechanistic model to simulate hepatocyte uptake of pitavastatin over time. There was excellent agreement between simulated and observed hepatocyte uptake of pitavastatin, indicating the suitability of this approach for translation of uptake from individual transporter-expressing cells to more holistic in vitro models. Subsequently, ft values were determined. The largest contributor to hepatocyte uptake of pitavastatin was OATP1B1, which correlates with what is known about the in vivo disposition of pitavastatin. The ft values were then used for evaluating in vitro-in vivo correlations of hepatic uptake inhibition with OATP inhibitors rifampicin and cyclosporine. Predictions were compared with previously reported plasma exposure changes of pitavastatin with these inhibitors. Although hepatic uptake inhibition of pitavastatin was 2-3-fold underpredicted, incorporation of scaling factors (SFs) into RAF values significantly improved the predictive ability. We propose that calibration of hepatocytes with standard transporter substrates and inhibitors would allow for determination of system-specific SFs, which could subsequently be used for refining predictions of clinical DDI potential for new chemical entities that undergo active hepatic uptake.
Full text links
Related Resources
Trending Papers
Challenges in Septic Shock: From New Hemodynamics to Blood Purification Therapies.Journal of Personalized Medicine 2024 Februrary 4
Molecular Targets of Novel Therapeutics for Diabetic Kidney Disease: A New Era of Nephroprotection.International Journal of Molecular Sciences 2024 April 4
The 'Ten Commandments' for the 2023 European Society of Cardiology guidelines for the management of endocarditis.European Heart Journal 2024 April 18
A Guide to the Use of Vasopressors and Inotropes for Patients in Shock.Journal of Intensive Care Medicine 2024 April 14
Get seemless 1-tap access through your institution/university
For the best experience, use the Read mobile app
All material on this website is protected by copyright, Copyright © 1994-2024 by WebMD LLC.
This website also contains material copyrighted by 3rd parties.
By using this service, you agree to our terms of use and privacy policy.
Your Privacy Choices
You can now claim free CME credits for this literature searchClaim now
Get seemless 1-tap access through your institution/university
For the best experience, use the Read mobile app