Hepatocellular shuttling and recirculation of sorafenib-glucuronide is dependent on Abcc2, Abcc3, and Oatp1a/1b

Aksana Vasilyeva, Selvi Durmus, Lie Li, Els Wagenaar, Shuiying Hu, Alice A. Gibson, John C. Panetta, Sridhar Mani, Alex Sparreboom, Sharyn D. Baker, Alfred H. Schinkel

Research output: Contribution to journalArticle

30 Scopus citations

Abstract

Recently, an efficient liver detoxification process dubbed "hepatocyte hopping" was proposed on the basis of findings with the endogenous compound, bilirubin glucuronide. According to this model, hepatocytic bilirubin glucuronide can follow a liver-to-blood shuttling loop via Abcc3 transporter-mediated efflux and subsequent Oatp1a/1b-mediated liver uptake. We hypothesized that glucuronide conjugates of xenobiotics, such as the anticancer drug sorafenib, can also undergo hepatocyte hopping. Using transporter-deficient mouse models, we show here that sorafenib-glucuronide can be extruded from hepatocytes into the bile by Abcc2 or back into the systemic circulation by Abcc3, and that it can be taken up efficiently again into neighboring hepatocytes by Oatp1a/1b. We further demonstrate that sorafenib-glucuronide excreted into the gut lumen can be cleaved by microbial enzymes to sorafenib, which is then reabsorbed, supporting its persistence in the systemic circulation. Our results suggest broad relevance of a hepatocyte shuttling process known as "hepatocyte hopping"- a novel concept in clinical pharmacology-for detoxification of targeted cancer drugs that undergo hepatic glucuronidation, such as sorafenib.

Original languageEnglish (US)
Pages (from-to)2729-2736
Number of pages8
JournalCancer Research
Volume75
Issue number13
DOIs
StatePublished - Jul 1 2015

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

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    Vasilyeva, A., Durmus, S., Li, L., Wagenaar, E., Hu, S., Gibson, A. A., Panetta, J. C., Mani, S., Sparreboom, A., Baker, S. D., & Schinkel, A. H. (2015). Hepatocellular shuttling and recirculation of sorafenib-glucuronide is dependent on Abcc2, Abcc3, and Oatp1a/1b. Cancer Research, 75(13), 2729-2736. https://doi.org/10.1158/0008-5472.CAN-15-0280