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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 October 13, 2020, DMD-AR-2020-000204; DOI: https://doi.org/10.1124/dmd.120.000204
Vineet Kumar
1Univiersity of Washington, United States of America
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Mengyue Yin
2University of Washington, United States of America
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Kazuya Ishida
3Gilead Sciences, United States
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Laurent Salphati
4Genentech, United States of America
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Cornelis E.C.A. Hop
4Genentech, United States of America
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Christopher Rowbottom
5DMPK, Biogen Inc., United States of America
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Guangqing Xiao
6Biogen Idec, United States of America
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Yurong Lai
7Drug Metabolism, Gilead Sciences Inc., United States of America
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Anita Mathias
8Clinical Pharmacology, Gilead Sciences, United States of America
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Xiaoyan Chu
9Drug Metabolism, Merck & Co., United States of America
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W. Griffith Humphreys
10PCO, Aranmore Pharma Consultancy, United States of America
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Mingxiang Liao
11DMPK, Takeda, United States of America
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Zsuzsanna Nerada
12SOLVO Biotechnology, Hungary
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Nóra Szilvásy
12SOLVO Biotechnology, Hungary
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Scott Heyward
13RnD, Bioreclamation IVT, United States of America
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Jashvant D. Unadkat
14Department of Pharmaceutics, University of Washington, United States of America
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  • For correspondence: jash@uw.edu
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Abstract

Suspended (SH), plated (PH) or sandwich-cultured human hepatocytes (SCHH) 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 if transporter-expressing cells (TEC) can accurately predict the CLuptake, in vivo of drugs. To do so, we determined the uptake CL (CLint,uptake,cells) of rosuvastatin (RSV) by TEC (OATPs/NTCP) and then scaled it to that in vivo by REF (the ratio of transporter abundance in human livers and TEC) determined by LC-MS/MS-based quantitative proteomics. Both the TEC and hepatocyte models did not meet our pre-defined success criteria of predicting within 2-fold the RSV CLuptake, in vivo value obtained from our PET imaging. However, the TEC performed better than the hepatocyte models. Interestingly, using REF, TEC successfully predicted RSV CLint,uptake,hep obtained by the hepatocyte models, suggesting that the underprediction of RSV CLuptake, in vivo by TEC and hepatocytes is due to an endogenous factor(s) not present in these in vitro models. Therefore, we determined if inclusion of plasma (or albumin) in TEC uptake studies, improved IVIVE of RSV CLuptake, in vivo. It did, but our predictions still fell shy of our pre-defined 2-fold lower boundary. Thus, 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 uptake CL of rosuvastatin, determined by PET imaging, cannot be accurately predicted from in vitro studies in transporter-expressing cells (scaled using REF) or human hepatocytes (scaled based on mg of protein per g of liver). This conclusion held irrespective of whether albumin or plasma was included in the in vitro studies. Thus, additional studies are needed to improve IVIVE of transporter-mediated drug CL.

  • hepatic uptake
  • in vitro-in vivo prediction (IVIVE)
  • transporters
  • Copyright © 2020 American Society for Pharmacology and Experimental Therapeutics
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Drug Metabolism and Disposition: 49 (3)
Drug Metabolism and Disposition
Vol. 49, Issue 3
1 Mar 2021
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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 October 13, 2020, DMD-AR-2020-000204; DOI: https://doi.org/10.1124/dmd.120.000204

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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 October 13, 2020, DMD-AR-2020-000204; DOI: https://doi.org/10.1124/dmd.120.000204
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