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Research ArticleArticle

Investigating the Impact of Albumin on the Liver Uptake of Pitavastatin and Warfarin in Nagase Analbuminemic Rats

Jae H Chang, Yi-Chen Chen, Jonathan Cheong, Robert S Jones and Jodie Pang
Drug Metabolism and Disposition September 6, 2019, dmd.119.088278; DOI: https://doi.org/10.1124/dmd.119.088278
Jae H Chang
Genentech
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  • For correspondence: jaechang@gmail.com
Yi-Chen Chen
Genentech
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Jonathan Cheong
Genentech
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Robert S Jones
Genentech
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Jodie Pang
Genentech
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Abstract

Albumin has been suggested to enhance the hepatic uptake of organic anion-transporting polypeptides (Oatps) substrates in various in vitro and liver perfusion models. However, it is not known if the interplay between albumin and Oatps is an experimental artifact, or whether this interaction occurs in vivo. The objective of this work was to investigate the hepatic uptake of warfarin and pitavastatin, which are both extensively bound to albumin, but only pitavastatin being an Oatp substrate. Experiments were conducted in Nagase analbuminemic rats (NAR) which exhibit reduced albumin levels compared with F344 (WT). The fraction unbound (fu) was 140- and 10-fold greater in NAR plasma for warfarin and pitavastatin, respectively, whereas no meaningful differences were observed with tissue binding. In vitro, pitavastatin uptake into hepatocytes reconstituted in WT plasma was 12- and 5-fold greater than when reconstituted in buffer or NAR plasma, respectively. In vivo, free tissue-to-free plasma ratios (Kp,u,u) from brain and liver in intact WT and NAR were not significantly different for warfarin. Contrarily, liver Kp,u,u of pitavastatin was 6-fold higher in WT animals which corresponded to 2.3-fold reduction in free plasma and 2.6-fold increase in free liver exposure. These results suggest that the enhanced hepatic uptake by albumin is not necessarily an experimental artifact but is also a relevant phenomenon in vivo. This work raises the possibility that additional plasma proteins may have similar impact on the function of other drug transporters, and that modulating plasma protein binding may exhibit meaningful clinical relevance in the disposition of drugs.

SIGNIFICANCE STATEMENT While the interplay between albumin and Oatps has been reported in hepatocytes and in liver perfusion studies, in vivo relevance of this interaction has not yet been elucidated. Utilizing NAR and its corresponding WT animal, the work presented here demonstrates that albumin may indeed enhance the hepatic uptake of pitavastatin in intact animals. In vivo demonstration of this interplay not only provides further justification for continued investigation into this particular mechanism, but also raises the possibility that other plasma proteins may affect additional drug transporters, and that modulating plasma protein binding may exhibit meaningful clinical relevance in the disposition of drugs.

  • animal models
  • animal/nonclinical/preclinical
  • genetically modified animal models
  • hepatocytes
  • liver/hepatic
  • protein binding
  • Transporter-mediated drug/metabolite disposition
  • Uptake transporters (OATP, OAT, OCT, PEPT, MCT, NTCP, ASBT, etc.)
  • The American Society for Pharmacology and Experimental Therapeutics
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Drug Metabolism and Disposition: 47 (12)
Drug Metabolism and Disposition
Vol. 47, Issue 12
1 Dec 2019
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Research ArticleArticle

Investigating the Impact of Albumin on the Liver Uptake of Pitavastatin and Warfarin in Nagase Analbuminemic Rats

Jae H Chang, Yi-Chen Chen, Jonathan Cheong, Robert S Jones and Jodie Pang
Drug Metabolism and Disposition September 6, 2019, dmd.119.088278; DOI: https://doi.org/10.1124/dmd.119.088278

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Research ArticleArticle

Investigating the Impact of Albumin on the Liver Uptake of Pitavastatin and Warfarin in Nagase Analbuminemic Rats

Jae H Chang, Yi-Chen Chen, Jonathan Cheong, Robert S Jones and Jodie Pang
Drug Metabolism and Disposition September 6, 2019, dmd.119.088278; DOI: https://doi.org/10.1124/dmd.119.088278
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