Predicting carrier-mediated hepatic disposition of rosuvastatin in man by scaling from individual transfected cell-lines in vitro using absolute transporter protein quantification and PBPK modeling.

Autor: Bosgra S; TNO (Netherlands Organisation for Applied Scientific Research), Zeist, The Netherlands. Electronic address: sieto.bosgra@tno.nl., van de Steeg E; TNO (Netherlands Organisation for Applied Scientific Research), Zeist, The Netherlands., Vlaming ML; TNO (Netherlands Organisation for Applied Scientific Research), Zeist, The Netherlands., Verhoeckx KC; TNO (Netherlands Organisation for Applied Scientific Research), Zeist, The Netherlands., Huisman MT; Janssen Pharmaceutica N.V., Beerse, Belgium., Verwei M; TNO (Netherlands Organisation for Applied Scientific Research), Zeist, The Netherlands., Wortelboer HM; TNO (Netherlands Organisation for Applied Scientific Research), Zeist, The Netherlands.
Jazyk: angličtina
Zdroj: European journal of pharmaceutical sciences : official journal of the European Federation for Pharmaceutical Sciences [Eur J Pharm Sci] 2014 Dec 18; Vol. 65, pp. 156-66. Date of Electronic Publication: 2014 Sep 28.
DOI: 10.1016/j.ejps.2014.09.007
Abstrakt: In contrast to primary hepatocytes, estimating carrier-mediated hepatic disposition by using a panel of single transfected cell-lines provides direct information on the contribution of the individual transporters to the net disposition. The most direct way to correct for differences in transporter abundance between cell-lines and tissue is by using absolute protein quantification. In the present study, the performance of this strategy to predict human hepatic uptake transport was investigated and compared with traditional scaling from primary human hepatocytes. Rosuvastatin was used as a model compound. The uptake activity was measured in HEK293 cell-lines stably overexpressing OATP1B1(∗)1a, OATP1B3 or OATP2B1, the major transporters involved in human hepatic uptake of rosuvastatin, or expressing OATP1B1(∗)15, associated with reduced hepatic uptake of rosuvastatin. The abundance of these transporter proteins in the outer membranes of HEK293-cells, in human primary hepatocytes and in human liver tissue was determined by LC-MS/MS. The measured activity, corrected for protein abundance and scaled to the whole liver, gave a very accurate prediction of the hepatic intrinsic clearance observed in vivo. Embedded in a PBPK model describing the hepatic disposition and enterohepatic circulation, the collective in vitro data resulted in a good explanation of the observed oral and intravenous pharmacokinetic profiles of rosuvastatin. The model allowed simulation of the effect of polymorphic variants of OATP1B1 on rosuvastatin pharmacokinetics. These results encourage a larger scale validation. This approach may facilitate prediction of drug-drug interactions, scaling of transporter processes across subpopulations (children, diseased patients), and may be extended to tissues for which primary cells may be more difficult to obtain.
(Copyright © 2014 Elsevier B.V. All rights reserved.)
Databáze: MEDLINE
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