Prediction of OATP1B1 and OATP1B3 Mediated Hepatic Uptake of Statins Based on Transporter Protein Expression and Activity Data

Kunze, A. and Huwyler, J. and Camenisch, G. and Poller, B.. (2014) Prediction of OATP1B1 and OATP1B3 Mediated Hepatic Uptake of Statins Based on Transporter Protein Expression and Activity Data. Drug metabolism and disposition, Vol. 42, H. 9. pp. 1514-1521.

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Official URL: http://edoc.unibas.ch/dok/A6337808

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Organic anion transporting polypeptides (OATP) 1B1 and OATP1B3 are drug transporters mediating the active hepatic uptake of their substrates. Since they exhibit overlapping substrate specificities the contribution of each isoform to the net hepatic uptake needs to be considered when predicting drug-drug interactions. The relative contribution of OATP1B1 and OATP1B3-mediated uptake of statins into hepatocytes was estimated based on either relative transporter protein expression data or relative activity data. Therefore, kinetics of eight statins and OATP1B1 and OATP1B3-specific reference substrates were determined in OATP1B1 and OATP1B3 expressing HEK293 cells and in human cryopreserved hepatocytes. Absolute OATP1B1 and OATP1B3 protein abundance was determined by liquid chromatography- tandem mass spectrometry in all expression systems. Transporter activity data generated in recombinant cell lines were extrapolated to hepatocyte values using relative transporter expression factors (REF) or relative activity factors (RAF). Our results showed a pronounced OATP1B1 and comparatively low OATP1B3 protein expression in the investigated hepatocyte lot. Based on REF-scaling, we demonstrated that the active hepatic uptake clearances of reference substrates, atorvastatin, pravastatin, rosuvastatin, and simvastatin were well predicted within two-fold error demonstrating that OATP1B1 and OATP1B3 were major contributors. For other statins, the net hepatic uptake clearance was under-predicted, suggesting the involvement of other hepatic uptake transporters. Summarized, we showed that REF and RAF-based predictions were highly similar indicating a direct transporter expression-activity relationship. Moreover, we demonstrated that the REF-scaling method provided a powerful tool to quantitatively assess the transporter-specific contributions to the net uptake clearance of statins in hepatocytes.
Faculties and Departments:05 Faculty of Science > Departement Pharmazeutische Wissenschaften > Pharmazie > Pharmazeutische Technologie (Huwyler)
UniBasel Contributors:Huwyler, Jörg
Item Type:Article, refereed
Article Subtype:Research Article
Publisher:Williams and Wilkins
Note:Publication type according to Uni Basel Research Database: Journal article
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Last Modified:06 Mar 2015 07:44
Deposited On:06 Mar 2015 07:44

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