Title
Drug-drug interactions between rosuvastatin and oral antidiabetic drugs occurring at the level of oatp1b1s
Author
van de Steeg, E.
Greupink, R.
Schreurs, M.
Nooijen, I.H.G.
Verhoeck, K.C.M.
Hanemaaijer, R.
Ripken, D.
Monshouwer, M.
Vlaming, M.L.H.
DeGroot, J.
Verwei, M.
Russel, F.G.M.
Huisman, M.T.
Wortelboer, H.M.
Publication year
2013
Abstract
Organic anion-transporting polypeptide 1B1 (OATP1B1) is an important hepatic uptake transporter, of which the polymorphic variant OATP1B1*15 (Asn130Asp and Val174Ala) has been associated with decreased transport activity. Rosuvastatin is an OATP1B1 substrate and often concomitantly prescribed with oral antidiabetics in the clinic. The aim of this study was to investigate possible drug-drug interactions between these drugs at the level of OATP1B1 and OATP1B1*15. We generated human embryonic kidney (HEK)293 cells stably overexpressing OATP1B1 or OATP1B1*15 that showed similar protein expression levels of OATP1B1 and OATP1B1*15 at the cell membrane as measured by liquid chromatography-tandem mass spectrometry. In HEK-OATP1B1*15 cells, the Vmax for OATP1B1-mediated transport of E217b-G (estradiol 17b-D-glucuronide) was decreased <60%, whereas Km values (Michaelis constant) were comparable. Uptake of rosuvastatin in HEK-OATP1B1 cells (Km 13.1 6 0.43 mM) was nearly absent in HEK-OATP1B1*15 cells. Interestingly, several oral antidiabetics (glyburide, glimepiride, troglitazone, pioglitazone, glipizide, gliclazide, and tolbutamide), but not metformin, were identified as significant inhibitors of the OATP1B1-mediated transport of rosuvastatin. The IC50 values for inhibition of E217b-G uptake were similar between OATP1B1 and OATP1B1*15. In conclusion, these studies indicate that several oral antidiabetic drugs affect the OATP1B1-mediated uptake of rosuvastatin in vitro. The next step will be to translate these data to the clinical situation, as it remains to be established whether the studied oral antidiabetics indeed affect the clinical pharmacokinetic profile of rosuvastatin in patients. Copyright © 2013 by The American Society for Pharmacology and Experimental Therapeutics.
Subject
Life
PHS - Pharmacokinetics & Human Studies
EELS - Earth, Environmental and Life Sciences
Biomedical Innovation
Biology
Healthy Living
To reference this document use:
http://resolver.tudelft.nl/uuid:458d857e-2086-4380-b430-dfcf74005815
DOI
https://doi.org/10.1124/dmd.112.049023
TNO identifier
470332
ISSN
0090-9556
Source
Drug Metabolism and Disposition, 41 (3), 592-601
Document type
article