Mechanistic Modeling of Pitavastatin Disposition in Sandwich-Cultured Human Hepatocytes: A Proteomics-Informed Bottom-Up Approach
2016 (English)In: Drug Metabolism And Disposition, ISSN 0090-9556, E-ISSN 1521-009X, Vol. 44, no 4, 505-516 p.Article in journal (Refereed) Published
Isolated human hepatocytes are commonly used to predict transporter-mediated clearance in vivo. Such predictions, however, do not provide estimations of transporter contributions and consequently do not allow predictions of the outcome resulting from a change in the activity of a certain transporter, e.g., by inhibition or a genetic variant with reduced function. Pitavastatin is a drug that is heavily dependent on hepatic transporters for its elimination and it is mainly excreted as unchanged drug in the bile. For this reason, pitavastatin was used as a model drug to demonstrate the applicability of a bottom-up approach to predict transporter-mediated disposition in sandwich-cultured human hepatocytes (SCHH), allowing for the estimation of transporter contributions. Transport experiments in transfected HEK293 cells and inverted membrane vesicles overexpressing each of the relevant transport proteins were used to generate parameter estimates for the mechanistic model. By adjusting for differences in transporter abundance between the in vitro systems and individual SCHH batches, the model successfully predicted time profiles of medium and intracellular accumulation. Our predictions of pitavastatin bile accumulation could, however, not be confirmed due to a very low biliary excretion of pitavastatin in relation to the hepatic uptake in our SCHH. This study is, to our knowledge, the first to successfully simulate transporter-mediated processes in a complex system such as SCHH at the level of individual transport proteins using a bottom-up approach.
Place, publisher, year, edition, pages
2016. Vol. 44, no 4, 505-516 p.
pitavastatin, SCHH, hepatocytes, drug transport, OATP, NTCP, hepatic uptake, Pgp, BCRP, MRP2, MRP3
Research subject Biopharmaceutics
IdentifiersURN: urn:nbn:se:uu:diva-241375DOI: 10.1124/dmd.115.066746ISI: 000372880600005PubMedID: 26842596OAI: oai:DiVA.org:uu-241375DiVA: diva2:778814
FunderSwedish Research Council, 2822Lars Hierta Memorial Foundation