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Research ArticleArticle

Prediction of Transporter-Mediated Rosuvastatin Hepatic Uptake Clearance and Drug Interaction in Humans Using Proteomics-Informed REF Approach

Vineet Kumar, Mengyue Yin, Kazuya Ishida, Laurent Salphati, Cornelis E.C.A. Hop, Christopher Rowbottom, Guangqing Xiao, Yurong Lai, Anita Mathias, Xiaoyan Chu, W. Griffith Humphreys, Mingxiang Liao, Zsuzsanna Nerada, Nóra Szilvásy, Scott Heyward and Jashvant D. Unadkat
Drug Metabolism and Disposition February 2021, 49 (2) 159-168; DOI: https://doi.org/10.1124/dmd.120.000204
Vineet Kumar
Department of Pharmaceutics, University of Washington, Seattle, Washington (V.K., M.Y., K.I., J.D.U.); Drug Metabolism and Pharmacokinetics, Genentech, Inc., South San Francisco, California (L.S., C.E.C.A.H.); DMPK, Biogen Idec, Cambridge, Massachusetts (C.R., G.X.); Clinical Pharmacology (A.M.) and Drug Metabolism (Y.L.), Gilead Sciences, Inc., Foster City, California; Pharmacokinetics, Pharmacodynamics and Drug Metabolism, Merck & Co. Inc., Kenilworth, New Jersey (X.C.); Bristol-Myers Squibb Company, Princeton, New Jersey (W.G.H.); Takeda Pharmaceuticals International Co., Cambridge, Massachusetts (M.L.); SOLVO Biotechnology, Budaörs, Hungary (Z.N., N.S.); and BioIVT, Baltimore, Maryland (S.H.)
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Mengyue Yin
Department of Pharmaceutics, University of Washington, Seattle, Washington (V.K., M.Y., K.I., J.D.U.); Drug Metabolism and Pharmacokinetics, Genentech, Inc., South San Francisco, California (L.S., C.E.C.A.H.); DMPK, Biogen Idec, Cambridge, Massachusetts (C.R., G.X.); Clinical Pharmacology (A.M.) and Drug Metabolism (Y.L.), Gilead Sciences, Inc., Foster City, California; Pharmacokinetics, Pharmacodynamics and Drug Metabolism, Merck & Co. Inc., Kenilworth, New Jersey (X.C.); Bristol-Myers Squibb Company, Princeton, New Jersey (W.G.H.); Takeda Pharmaceuticals International Co., Cambridge, Massachusetts (M.L.); SOLVO Biotechnology, Budaörs, Hungary (Z.N., N.S.); and BioIVT, Baltimore, Maryland (S.H.)
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Kazuya Ishida
Department of Pharmaceutics, University of Washington, Seattle, Washington (V.K., M.Y., K.I., J.D.U.); Drug Metabolism and Pharmacokinetics, Genentech, Inc., South San Francisco, California (L.S., C.E.C.A.H.); DMPK, Biogen Idec, Cambridge, Massachusetts (C.R., G.X.); Clinical Pharmacology (A.M.) and Drug Metabolism (Y.L.), Gilead Sciences, Inc., Foster City, California; Pharmacokinetics, Pharmacodynamics and Drug Metabolism, Merck & Co. Inc., Kenilworth, New Jersey (X.C.); Bristol-Myers Squibb Company, Princeton, New Jersey (W.G.H.); Takeda Pharmaceuticals International Co., Cambridge, Massachusetts (M.L.); SOLVO Biotechnology, Budaörs, Hungary (Z.N., N.S.); and BioIVT, Baltimore, Maryland (S.H.)
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Laurent Salphati
Department of Pharmaceutics, University of Washington, Seattle, Washington (V.K., M.Y., K.I., J.D.U.); Drug Metabolism and Pharmacokinetics, Genentech, Inc., South San Francisco, California (L.S., C.E.C.A.H.); DMPK, Biogen Idec, Cambridge, Massachusetts (C.R., G.X.); Clinical Pharmacology (A.M.) and Drug Metabolism (Y.L.), Gilead Sciences, Inc., Foster City, California; Pharmacokinetics, Pharmacodynamics and Drug Metabolism, Merck & Co. Inc., Kenilworth, New Jersey (X.C.); Bristol-Myers Squibb Company, Princeton, New Jersey (W.G.H.); Takeda Pharmaceuticals International Co., Cambridge, Massachusetts (M.L.); SOLVO Biotechnology, Budaörs, Hungary (Z.N., N.S.); and BioIVT, Baltimore, Maryland (S.H.)
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Cornelis E.C.A. Hop
Department of Pharmaceutics, University of Washington, Seattle, Washington (V.K., M.Y., K.I., J.D.U.); Drug Metabolism and Pharmacokinetics, Genentech, Inc., South San Francisco, California (L.S., C.E.C.A.H.); DMPK, Biogen Idec, Cambridge, Massachusetts (C.R., G.X.); Clinical Pharmacology (A.M.) and Drug Metabolism (Y.L.), Gilead Sciences, Inc., Foster City, California; Pharmacokinetics, Pharmacodynamics and Drug Metabolism, Merck & Co. Inc., Kenilworth, New Jersey (X.C.); Bristol-Myers Squibb Company, Princeton, New Jersey (W.G.H.); Takeda Pharmaceuticals International Co., Cambridge, Massachusetts (M.L.); SOLVO Biotechnology, Budaörs, Hungary (Z.N., N.S.); and BioIVT, Baltimore, Maryland (S.H.)
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Christopher Rowbottom
Department of Pharmaceutics, University of Washington, Seattle, Washington (V.K., M.Y., K.I., J.D.U.); Drug Metabolism and Pharmacokinetics, Genentech, Inc., South San Francisco, California (L.S., C.E.C.A.H.); DMPK, Biogen Idec, Cambridge, Massachusetts (C.R., G.X.); Clinical Pharmacology (A.M.) and Drug Metabolism (Y.L.), Gilead Sciences, Inc., Foster City, California; Pharmacokinetics, Pharmacodynamics and Drug Metabolism, Merck & Co. Inc., Kenilworth, New Jersey (X.C.); Bristol-Myers Squibb Company, Princeton, New Jersey (W.G.H.); Takeda Pharmaceuticals International Co., Cambridge, Massachusetts (M.L.); SOLVO Biotechnology, Budaörs, Hungary (Z.N., N.S.); and BioIVT, Baltimore, Maryland (S.H.)
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Guangqing Xiao
Department of Pharmaceutics, University of Washington, Seattle, Washington (V.K., M.Y., K.I., J.D.U.); Drug Metabolism and Pharmacokinetics, Genentech, Inc., South San Francisco, California (L.S., C.E.C.A.H.); DMPK, Biogen Idec, Cambridge, Massachusetts (C.R., G.X.); Clinical Pharmacology (A.M.) and Drug Metabolism (Y.L.), Gilead Sciences, Inc., Foster City, California; Pharmacokinetics, Pharmacodynamics and Drug Metabolism, Merck & Co. Inc., Kenilworth, New Jersey (X.C.); Bristol-Myers Squibb Company, Princeton, New Jersey (W.G.H.); Takeda Pharmaceuticals International Co., Cambridge, Massachusetts (M.L.); SOLVO Biotechnology, Budaörs, Hungary (Z.N., N.S.); and BioIVT, Baltimore, Maryland (S.H.)
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Yurong Lai
Department of Pharmaceutics, University of Washington, Seattle, Washington (V.K., M.Y., K.I., J.D.U.); Drug Metabolism and Pharmacokinetics, Genentech, Inc., South San Francisco, California (L.S., C.E.C.A.H.); DMPK, Biogen Idec, Cambridge, Massachusetts (C.R., G.X.); Clinical Pharmacology (A.M.) and Drug Metabolism (Y.L.), Gilead Sciences, Inc., Foster City, California; Pharmacokinetics, Pharmacodynamics and Drug Metabolism, Merck & Co. Inc., Kenilworth, New Jersey (X.C.); Bristol-Myers Squibb Company, Princeton, New Jersey (W.G.H.); Takeda Pharmaceuticals International Co., Cambridge, Massachusetts (M.L.); SOLVO Biotechnology, Budaörs, Hungary (Z.N., N.S.); and BioIVT, Baltimore, Maryland (S.H.)
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Anita Mathias
Department of Pharmaceutics, University of Washington, Seattle, Washington (V.K., M.Y., K.I., J.D.U.); Drug Metabolism and Pharmacokinetics, Genentech, Inc., South San Francisco, California (L.S., C.E.C.A.H.); DMPK, Biogen Idec, Cambridge, Massachusetts (C.R., G.X.); Clinical Pharmacology (A.M.) and Drug Metabolism (Y.L.), Gilead Sciences, Inc., Foster City, California; Pharmacokinetics, Pharmacodynamics and Drug Metabolism, Merck & Co. Inc., Kenilworth, New Jersey (X.C.); Bristol-Myers Squibb Company, Princeton, New Jersey (W.G.H.); Takeda Pharmaceuticals International Co., Cambridge, Massachusetts (M.L.); SOLVO Biotechnology, Budaörs, Hungary (Z.N., N.S.); and BioIVT, Baltimore, Maryland (S.H.)
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Xiaoyan Chu
Department of Pharmaceutics, University of Washington, Seattle, Washington (V.K., M.Y., K.I., J.D.U.); Drug Metabolism and Pharmacokinetics, Genentech, Inc., South San Francisco, California (L.S., C.E.C.A.H.); DMPK, Biogen Idec, Cambridge, Massachusetts (C.R., G.X.); Clinical Pharmacology (A.M.) and Drug Metabolism (Y.L.), Gilead Sciences, Inc., Foster City, California; Pharmacokinetics, Pharmacodynamics and Drug Metabolism, Merck & Co. Inc., Kenilworth, New Jersey (X.C.); Bristol-Myers Squibb Company, Princeton, New Jersey (W.G.H.); Takeda Pharmaceuticals International Co., Cambridge, Massachusetts (M.L.); SOLVO Biotechnology, Budaörs, Hungary (Z.N., N.S.); and BioIVT, Baltimore, Maryland (S.H.)
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W. Griffith Humphreys
Department of Pharmaceutics, University of Washington, Seattle, Washington (V.K., M.Y., K.I., J.D.U.); Drug Metabolism and Pharmacokinetics, Genentech, Inc., South San Francisco, California (L.S., C.E.C.A.H.); DMPK, Biogen Idec, Cambridge, Massachusetts (C.R., G.X.); Clinical Pharmacology (A.M.) and Drug Metabolism (Y.L.), Gilead Sciences, Inc., Foster City, California; Pharmacokinetics, Pharmacodynamics and Drug Metabolism, Merck & Co. Inc., Kenilworth, New Jersey (X.C.); Bristol-Myers Squibb Company, Princeton, New Jersey (W.G.H.); Takeda Pharmaceuticals International Co., Cambridge, Massachusetts (M.L.); SOLVO Biotechnology, Budaörs, Hungary (Z.N., N.S.); and BioIVT, Baltimore, Maryland (S.H.)
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Mingxiang Liao
Department of Pharmaceutics, University of Washington, Seattle, Washington (V.K., M.Y., K.I., J.D.U.); Drug Metabolism and Pharmacokinetics, Genentech, Inc., South San Francisco, California (L.S., C.E.C.A.H.); DMPK, Biogen Idec, Cambridge, Massachusetts (C.R., G.X.); Clinical Pharmacology (A.M.) and Drug Metabolism (Y.L.), Gilead Sciences, Inc., Foster City, California; Pharmacokinetics, Pharmacodynamics and Drug Metabolism, Merck & Co. Inc., Kenilworth, New Jersey (X.C.); Bristol-Myers Squibb Company, Princeton, New Jersey (W.G.H.); Takeda Pharmaceuticals International Co., Cambridge, Massachusetts (M.L.); SOLVO Biotechnology, Budaörs, Hungary (Z.N., N.S.); and BioIVT, Baltimore, Maryland (S.H.)
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Zsuzsanna Nerada
Department of Pharmaceutics, University of Washington, Seattle, Washington (V.K., M.Y., K.I., J.D.U.); Drug Metabolism and Pharmacokinetics, Genentech, Inc., South San Francisco, California (L.S., C.E.C.A.H.); DMPK, Biogen Idec, Cambridge, Massachusetts (C.R., G.X.); Clinical Pharmacology (A.M.) and Drug Metabolism (Y.L.), Gilead Sciences, Inc., Foster City, California; Pharmacokinetics, Pharmacodynamics and Drug Metabolism, Merck & Co. Inc., Kenilworth, New Jersey (X.C.); Bristol-Myers Squibb Company, Princeton, New Jersey (W.G.H.); Takeda Pharmaceuticals International Co., Cambridge, Massachusetts (M.L.); SOLVO Biotechnology, Budaörs, Hungary (Z.N., N.S.); and BioIVT, Baltimore, Maryland (S.H.)
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Nóra Szilvásy
Department of Pharmaceutics, University of Washington, Seattle, Washington (V.K., M.Y., K.I., J.D.U.); Drug Metabolism and Pharmacokinetics, Genentech, Inc., South San Francisco, California (L.S., C.E.C.A.H.); DMPK, Biogen Idec, Cambridge, Massachusetts (C.R., G.X.); Clinical Pharmacology (A.M.) and Drug Metabolism (Y.L.), Gilead Sciences, Inc., Foster City, California; Pharmacokinetics, Pharmacodynamics and Drug Metabolism, Merck & Co. Inc., Kenilworth, New Jersey (X.C.); Bristol-Myers Squibb Company, Princeton, New Jersey (W.G.H.); Takeda Pharmaceuticals International Co., Cambridge, Massachusetts (M.L.); SOLVO Biotechnology, Budaörs, Hungary (Z.N., N.S.); and BioIVT, Baltimore, Maryland (S.H.)
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Scott Heyward
Department of Pharmaceutics, University of Washington, Seattle, Washington (V.K., M.Y., K.I., J.D.U.); Drug Metabolism and Pharmacokinetics, Genentech, Inc., South San Francisco, California (L.S., C.E.C.A.H.); DMPK, Biogen Idec, Cambridge, Massachusetts (C.R., G.X.); Clinical Pharmacology (A.M.) and Drug Metabolism (Y.L.), Gilead Sciences, Inc., Foster City, California; Pharmacokinetics, Pharmacodynamics and Drug Metabolism, Merck & Co. Inc., Kenilworth, New Jersey (X.C.); Bristol-Myers Squibb Company, Princeton, New Jersey (W.G.H.); Takeda Pharmaceuticals International Co., Cambridge, Massachusetts (M.L.); SOLVO Biotechnology, Budaörs, Hungary (Z.N., N.S.); and BioIVT, Baltimore, Maryland (S.H.)
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Jashvant D. Unadkat
Department of Pharmaceutics, University of Washington, Seattle, Washington (V.K., M.Y., K.I., J.D.U.); Drug Metabolism and Pharmacokinetics, Genentech, Inc., South San Francisco, California (L.S., C.E.C.A.H.); DMPK, Biogen Idec, Cambridge, Massachusetts (C.R., G.X.); Clinical Pharmacology (A.M.) and Drug Metabolism (Y.L.), Gilead Sciences, Inc., Foster City, California; Pharmacokinetics, Pharmacodynamics and Drug Metabolism, Merck & Co. Inc., Kenilworth, New Jersey (X.C.); Bristol-Myers Squibb Company, Princeton, New Jersey (W.G.H.); Takeda Pharmaceuticals International Co., Cambridge, Massachusetts (M.L.); SOLVO Biotechnology, Budaörs, Hungary (Z.N., N.S.); and BioIVT, Baltimore, Maryland (S.H.)
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Abstract

Suspended, plated, or sandwich-cultured human hepatocytes are routinely used for in vitro to in vivo extrapolation (IVIVE) of transporter-mediated hepatic clearance (CL) of drugs. However, these hepatocyte models have been reported to underpredict transporter-mediated in vivo hepatic uptake CL (CLuptake,in vivo) of some drugs. Therefore, we determined whether transporter-expressing cells (TECs) can accurately predict the CLuptake,in vivo of drugs. To do so, we determined the uptake CL (CLint,uptake,cells) of rosuvastatin (RSV) by TECs (organic anion transporting polypeptides/Na+-taurocholate cotransporting polypeptide) and then scaled it to that in vivo by relative expression factor (REF) (the ratio of transporter abundance in human livers and TEC) determined by liquid chromatography tandem mass spectrometry–based quantitative proteomics. Both the TEC and hepatocyte models did not meet our predefined success criteria of predicting within 2-fold the RSV CLuptake,in vivo value obtained from our positron emission tomography (PET) imaging. However, the TEC performed better than the hepatocyte models. Interestingly, using REF, TECs successfully predicted RSV CLint,uptake,hep obtained by the hepatocyte models, suggesting that the underprediction of RSV CLuptake,in vivo by TECs and hepatocytes is due to endogenous factor(s) not present in these in vitro models. Therefore, we determined whether inclusion of plasma (or albumin) in TEC uptake studies improved IVIVE of RSV CLuptake,in vivo. It did, and our predictions were close to or just fell above our lower 2-fold acceptance boundary. Despite this success, additional studies are needed to improve transporter-mediated IVIVE of hepatic uptake CL of drugs. However, using REF and TEC, we successfully predicted the magnitude of PET-imaged inhibition of RSV CLuptake,in vivo by cyclosporine A.

SIGNIFICANCE STATEMENT We showed that the in vivo transporter-mediated hepatic uptake CL of rosuvastatin, determined by PET imaging, can be predicted (within 2-fold) from in vitro studies in transporter-expressing cells (TECs) (scaled using REF), but only when plasma proteins were included in the in vitro studies. This conclusion did not hold when plasma proteins were absent in the TEC or human hepatocyte studies. Thus, additional studies are needed to improve in vitro to in vivo extrapolation of transporter-mediated drug CL.

Footnotes

    • Received August 4, 2020.
    • Accepted September 24, 2020.
  • ↵1 Current affiliation: Gilead Sciences, Inc., Foster City, California.

  • ↵2 Current affiliation: Sunovion Pharmaceuticals, Inc., Marlborough, Massachusetts.

  • ↵3 Current affiliation: Aranmore Pharma Consultant, Trenton, New Jersey.

  • ↵4 Current affiliation: Clovis Oncology, San Francisco, California.

  • V.K. and M.Y. were supported in part by the Simcyp Grant and Partnership Scheme and University of Washington Research Affiliate Program on Transporters (UWRAPT) funded by Genentech, Biogen, Gilead, Merck, Bristol-Myers Squibb, Pfizer, and Takeda.

  • https://doi.org/10.1124/dmd.120.000204.

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

  • Copyright © 2021 by The American Society for Pharmacology and Experimental Therapeutics
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Drug Metabolism and Disposition: 49 (2)
Drug Metabolism and Disposition
Vol. 49, Issue 2
1 Feb 2021
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Research ArticleArticle

IVIVE of Rosuvastatin Hepatic Clearance in Human

Vineet Kumar, Mengyue Yin, Kazuya Ishida, Laurent Salphati, Cornelis E.C.A. Hop, Christopher Rowbottom, Guangqing Xiao, Yurong Lai, Anita Mathias, Xiaoyan Chu, W. Griffith Humphreys, Mingxiang Liao, Zsuzsanna Nerada, Nóra Szilvásy, Scott Heyward and Jashvant D. Unadkat
Drug Metabolism and Disposition February 1, 2021, 49 (2) 159-168; DOI: https://doi.org/10.1124/dmd.120.000204

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Research ArticleArticle

IVIVE of Rosuvastatin Hepatic Clearance in Human

Vineet Kumar, Mengyue Yin, Kazuya Ishida, Laurent Salphati, Cornelis E.C.A. Hop, Christopher Rowbottom, Guangqing Xiao, Yurong Lai, Anita Mathias, Xiaoyan Chu, W. Griffith Humphreys, Mingxiang Liao, Zsuzsanna Nerada, Nóra Szilvásy, Scott Heyward and Jashvant D. Unadkat
Drug Metabolism and Disposition February 1, 2021, 49 (2) 159-168; DOI: https://doi.org/10.1124/dmd.120.000204
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