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Research ArticleArticle

Drug-Drug Interactions between Rosuvastatin and Oral Antidiabetic Drugs Occurring at the Level of OATP1B1

E. van de Steeg, R. Greupink, M. Schreurs, I.H.G. Nooijen, K.C.M. Verhoeckx, R. Hanemaaijer, D. Ripken, M. Monshouwer, M.L.H. Vlaming, J. DeGroot, M. Verwei, F.G.M. Russel, M.T. Huisman and H.M. Wortelboer
Drug Metabolism and Disposition March 2013, 41 (3) 592-601; DOI: https://doi.org/10.1124/dmd.112.049023
E. van de Steeg
TNO, Zeist, The Netherlands (E.S., I.H.G.N., K.C.M.V., R.H., D.R., M.L.H.V., J.D., M.V., H.M.W.); Pharmacology and Toxicology, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands (R.G., M.S., F.G.M.R.); and Drug Metabolism and Pharmacokinetics, Janssen Pharmaceutical Companies of Johnson & Johnson, Beerse, Belgium (M.M., M.T.H.)
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R. Greupink
TNO, Zeist, The Netherlands (E.S., I.H.G.N., K.C.M.V., R.H., D.R., M.L.H.V., J.D., M.V., H.M.W.); Pharmacology and Toxicology, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands (R.G., M.S., F.G.M.R.); and Drug Metabolism and Pharmacokinetics, Janssen Pharmaceutical Companies of Johnson & Johnson, Beerse, Belgium (M.M., M.T.H.)
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M. Schreurs
TNO, Zeist, The Netherlands (E.S., I.H.G.N., K.C.M.V., R.H., D.R., M.L.H.V., J.D., M.V., H.M.W.); Pharmacology and Toxicology, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands (R.G., M.S., F.G.M.R.); and Drug Metabolism and Pharmacokinetics, Janssen Pharmaceutical Companies of Johnson & Johnson, Beerse, Belgium (M.M., M.T.H.)
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I.H.G. Nooijen
TNO, Zeist, The Netherlands (E.S., I.H.G.N., K.C.M.V., R.H., D.R., M.L.H.V., J.D., M.V., H.M.W.); Pharmacology and Toxicology, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands (R.G., M.S., F.G.M.R.); and Drug Metabolism and Pharmacokinetics, Janssen Pharmaceutical Companies of Johnson & Johnson, Beerse, Belgium (M.M., M.T.H.)
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K.C.M. Verhoeckx
TNO, Zeist, The Netherlands (E.S., I.H.G.N., K.C.M.V., R.H., D.R., M.L.H.V., J.D., M.V., H.M.W.); Pharmacology and Toxicology, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands (R.G., M.S., F.G.M.R.); and Drug Metabolism and Pharmacokinetics, Janssen Pharmaceutical Companies of Johnson & Johnson, Beerse, Belgium (M.M., M.T.H.)
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R. Hanemaaijer
TNO, Zeist, The Netherlands (E.S., I.H.G.N., K.C.M.V., R.H., D.R., M.L.H.V., J.D., M.V., H.M.W.); Pharmacology and Toxicology, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands (R.G., M.S., F.G.M.R.); and Drug Metabolism and Pharmacokinetics, Janssen Pharmaceutical Companies of Johnson & Johnson, Beerse, Belgium (M.M., M.T.H.)
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D. Ripken
TNO, Zeist, The Netherlands (E.S., I.H.G.N., K.C.M.V., R.H., D.R., M.L.H.V., J.D., M.V., H.M.W.); Pharmacology and Toxicology, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands (R.G., M.S., F.G.M.R.); and Drug Metabolism and Pharmacokinetics, Janssen Pharmaceutical Companies of Johnson & Johnson, Beerse, Belgium (M.M., M.T.H.)
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M. Monshouwer
TNO, Zeist, The Netherlands (E.S., I.H.G.N., K.C.M.V., R.H., D.R., M.L.H.V., J.D., M.V., H.M.W.); Pharmacology and Toxicology, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands (R.G., M.S., F.G.M.R.); and Drug Metabolism and Pharmacokinetics, Janssen Pharmaceutical Companies of Johnson & Johnson, Beerse, Belgium (M.M., M.T.H.)
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M.L.H. Vlaming
TNO, Zeist, The Netherlands (E.S., I.H.G.N., K.C.M.V., R.H., D.R., M.L.H.V., J.D., M.V., H.M.W.); Pharmacology and Toxicology, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands (R.G., M.S., F.G.M.R.); and Drug Metabolism and Pharmacokinetics, Janssen Pharmaceutical Companies of Johnson & Johnson, Beerse, Belgium (M.M., M.T.H.)
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J. DeGroot
TNO, Zeist, The Netherlands (E.S., I.H.G.N., K.C.M.V., R.H., D.R., M.L.H.V., J.D., M.V., H.M.W.); Pharmacology and Toxicology, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands (R.G., M.S., F.G.M.R.); and Drug Metabolism and Pharmacokinetics, Janssen Pharmaceutical Companies of Johnson & Johnson, Beerse, Belgium (M.M., M.T.H.)
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M. Verwei
TNO, Zeist, The Netherlands (E.S., I.H.G.N., K.C.M.V., R.H., D.R., M.L.H.V., J.D., M.V., H.M.W.); Pharmacology and Toxicology, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands (R.G., M.S., F.G.M.R.); and Drug Metabolism and Pharmacokinetics, Janssen Pharmaceutical Companies of Johnson & Johnson, Beerse, Belgium (M.M., M.T.H.)
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F.G.M. Russel
TNO, Zeist, The Netherlands (E.S., I.H.G.N., K.C.M.V., R.H., D.R., M.L.H.V., J.D., M.V., H.M.W.); Pharmacology and Toxicology, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands (R.G., M.S., F.G.M.R.); and Drug Metabolism and Pharmacokinetics, Janssen Pharmaceutical Companies of Johnson & Johnson, Beerse, Belgium (M.M., M.T.H.)
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M.T. Huisman
TNO, Zeist, The Netherlands (E.S., I.H.G.N., K.C.M.V., R.H., D.R., M.L.H.V., J.D., M.V., H.M.W.); Pharmacology and Toxicology, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands (R.G., M.S., F.G.M.R.); and Drug Metabolism and Pharmacokinetics, Janssen Pharmaceutical Companies of Johnson & Johnson, Beerse, Belgium (M.M., M.T.H.)
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H.M. Wortelboer
TNO, Zeist, The Netherlands (E.S., I.H.G.N., K.C.M.V., R.H., D.R., M.L.H.V., J.D., M.V., H.M.W.); Pharmacology and Toxicology, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands (R.G., M.S., F.G.M.R.); and Drug Metabolism and Pharmacokinetics, Janssen Pharmaceutical Companies of Johnson & Johnson, Beerse, Belgium (M.M., M.T.H.)
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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 E217β-G (estradiol 17β-d-glucuronide) was decreased >60%, whereas Km values (Michaelis constant) were comparable. Uptake of rosuvastatin in HEK-OATP1B1 cells (Km 13.1 ± 0.43 μM) 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 E217β-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.

Footnotes

  • E.S. was supported by a grant of the Centre for Medical Systems Biology; and R.G. and M.S. were supported by an unconditional grant of Janssen Pharmaceutical Companies of Johnson & Johnson. The HEK-OATP1B1 and HEK-OATP1B1*15 cells used in these studies were generated and characterized within a collaboration between TNO, Janssen Pharmaceutical Companies of Johnson & Johnson, and Radboud University Nijmegen Medical Centre, partly funded by The Netherlands Ministry of Economic Affairs [project number EZ1560].

  • E.S. and R.G. contributed equally to this manuscript.

  • dx.doi.org/10.1124/dmd.112.049023.

  • ↵Embedded ImageThis article has supplemental material available at dmd.aspetjournals.org.

  • Received September 12, 2012.
  • Accepted December 17, 2012.
  • Copyright © 2013 by The American Society for Pharmacology and Experimental Therapeutics
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Drug Metabolism and Disposition: 41 (3)
Drug Metabolism and Disposition
Vol. 41, Issue 3
1 Mar 2013
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Research ArticleArticle

Drug-Drug Interaction with Oral Antidiabetics

E. van de Steeg, R. Greupink, M. Schreurs, I.H.G. Nooijen, K.C.M. Verhoeckx, R. Hanemaaijer, D. Ripken, M. Monshouwer, M.L.H. Vlaming, J. DeGroot, M. Verwei, F.G.M. Russel, M.T. Huisman and H.M. Wortelboer
Drug Metabolism and Disposition March 1, 2013, 41 (3) 592-601; DOI: https://doi.org/10.1124/dmd.112.049023

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Research ArticleArticle

Drug-Drug Interaction with Oral Antidiabetics

E. van de Steeg, R. Greupink, M. Schreurs, I.H.G. Nooijen, K.C.M. Verhoeckx, R. Hanemaaijer, D. Ripken, M. Monshouwer, M.L.H. Vlaming, J. DeGroot, M. Verwei, F.G.M. Russel, M.T. Huisman and H.M. Wortelboer
Drug Metabolism and Disposition March 1, 2013, 41 (3) 592-601; DOI: https://doi.org/10.1124/dmd.112.049023
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