title: Hepatocellular Shuttling and Recirculation of Sorafenib-Glucuronide Is Dependent on Abcc2, Abcc3, and Oatp1a/1b.
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.
authors.affiliation: Department of Pharmaceutical Sciences, St. Jude Children's Research Hospital, Memphis, Tennessee.
authors.forename: Aksana
authors.initials: A
authors.lastname: Vasilyeva
authors.affiliation: Division of Molecular Oncology, The Netherlands Cancer Institute, Amsterdam, the Netherlands.
authors.forename: Selvi
authors.initials: S
authors.lastname: Durmus
authors.affiliation: Department of Pharmaceutical Sciences, St. Jude Children's Research Hospital, Memphis, Tennessee.
authors.forename: Lie
authors.initials: L
authors.lastname: Li
authors.affiliation: Division of Molecular Oncology, The Netherlands Cancer Institute, Amsterdam, the Netherlands.
authors.forename: Els
authors.initials: E
authors.lastname: Wagenaar
authors.affiliation: Department of Pharmaceutical Sciences, St. Jude Children's Research Hospital, Memphis, Tennessee.
authors.forename: Shuiying
authors.initials: S
authors.lastname: Hu
authors.affiliation: Department of Pharmaceutical Sciences, St. Jude Children's Research Hospital, Memphis, Tennessee.
authors.forename: Alice A
authors.initials: AA
authors.lastname: Gibson
authors.affiliation: Department of Pharmaceutical Sciences, St. Jude Children's Research Hospital, Memphis, Tennessee.
authors.forename: John C
authors.initials: JC
authors.lastname: Panetta
authors.affiliation: Department of Medicine, Albert Einstein College of Medicine, Bronx, New York.
authors.forename: Sridhar
authors.initials: S
authors.lastname: Mani
authors.affiliation: Department of Pharmaceutical Sciences, St. Jude Children's Research Hospital, Memphis, Tennessee.
authors.forename: Alex
authors.initials: A
authors.lastname: Sparreboom
authors.affiliation: Department of Pharmaceutical Sciences, St. Jude Children's Research Hospital, Memphis, Tennessee. sharyn.baker@stjude.org.
authors.forename: Sharyn D
authors.initials: SD
authors.lastname: Baker
authors.affiliation: Division of Molecular Oncology, The Netherlands Cancer Institute, Amsterdam, the Netherlands.
authors.forename: Alfred H
authors.initials: AH
authors.lastname: Schinkel
mesh_terms: D000818:Animals; D005260:Female; D005966:Glucuronidase / Q000378:metabolism; D020719:Glucuronides / Q000097:blood / Q000378:metabolism*; D022781:Hepatocytes / Q000378:metabolism*; D006801:Humans; D007422:Intestines / Q000201:enzymology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D000089762:Multidrug Resistance-Associated Protein 2; D027425:ATP-Binding Cassette, Sub-Family C Proteins / Q000378:metabolism*; D009536:Niacinamide / Q000031:analogs & derivatives* / Q000097:blood / Q000493:pharmacokinetics; D027701:Organic Cation Transport Proteins / Q000378:metabolism*; D010671:Phenylurea Compounds / Q000097:blood / Q000493:pharmacokinetics*; D051381:Rats; D061987:Sf9 Cells; D000077157:Sorafenib
chemical_list: D005966:Glucuronidase; D020719:Glucuronides; D000089762:Multidrug Resistance-Associated Protein 2; D027425:ATP-Binding Cassette, Sub-Family C Proteins; D009536:Niacinamide; D027701:Organic Cation Transport Proteins; D010671:Phenylurea Compounds; D000077157:Sorafenib; C000715087:ABCC2 protein, human; C114462:multidrug resistance-associated protein 3