title: Influence of OATP1B1 Function on the Disposition of Sorafenib-β-D-Glucuronide.
abstract: The oral multikinase inhibitor sorafenib undergoes extensive UGT1A9-mediated formation of sorafenib-β-D-glucuronide (SG). Using transporter-deficient mouse models, it was previously established that SG can be extruded into bile by ABCC2 or follow a liver-to-blood shuttling loop via ABCC3-mediated efflux into the systemic circulation, and subsequent uptake in neighboring hepatocytes by OATP1B-type transporters. Here we evaluated the possibility that this unusual process, called hepatocyte hopping, is also operational in humans and can be modulated through pharmacological inhibition. We found that SG transport by OATP1B1 or murine Oatp1b2 was effectively inhibited by rifampin, and that this agent can significantly increase plasma levels of SG in wildtype mice, but not in Oatp1b2-deficient animals. In human subjects receiving sorafenib, rifampin acutely increased the systemic exposure to SG. Our study emphasizes the need to consider hepatic handling of xenobiotic glucuronides in the design of drug-drug interaction studies of agents that undergo extensive phase II conjugation.
authors.affiliation: Department of Medical Oncology, Erasmus MC Cancer Institute, Wytemaweg, Rotterdam, The Netherlands.
authors.forename: S
authors.initials: S
authors.lastname: Bins
authors.affiliation: Department of Medical Oncology, Erasmus MC Cancer Institute, Wytemaweg, Rotterdam, The Netherlands.
authors.forename: L
authors.initials: L
authors.lastname: van Doorn
authors.affiliation: Division of Pharmaceutics and Pharmaceutical Chemistry, College of Pharmacy, Ohio State University, Columbus, Ohio, USA.
authors.forename: M A
authors.initials: MA
authors.lastname: Phelps
authors.affiliation: Division of Pharmaceutics and Pharmaceutical Chemistry, College of Pharmacy, Ohio State University, Columbus, Ohio, USA.
authors.forename: A A
authors.initials: AA
authors.lastname: Gibson
authors.affiliation: Division of Pharmaceutics and Pharmaceutical Chemistry, College of Pharmacy, Ohio State University, Columbus, Ohio, USA.
authors.forename: S
authors.initials: S
authors.lastname: Hu
authors.affiliation: Department of Pharmaceutical Sciences, St. Jude Children's Research Hospital, Memphis, Tennessee, USA.
authors.forename: L
authors.initials: L
authors.lastname: Li
authors.affiliation: Department of Pharmaceutical Sciences, St. Jude Children's Research Hospital, Memphis, Tennessee, USA.
authors.forename: A
authors.initials: A
authors.lastname: Vasilyeva
authors.affiliation: Department of Pharmaceutical Sciences, St. Jude Children's Research Hospital, Memphis, Tennessee, USA.
authors.forename: G
authors.initials: G
authors.lastname: Du
authors.affiliation: Department of Internal Medicine, St. Franciscus Gasthuis, Rotterdam, The Netherlands.
authors.forename: P
authors.initials: P
authors.lastname: Hamberg
authors.affiliation: Department of Medical Oncology, Erasmus MC Cancer Institute, Wytemaweg, Rotterdam, The Netherlands.
authors.forename: Falm
authors.initials: F
authors.lastname: Eskens
authors.affiliation: Department of Medical Oncology, Erasmus MC Cancer Institute, Wytemaweg, Rotterdam, The Netherlands.
authors.forename: P
authors.initials: P
authors.lastname: de Bruijn
authors.affiliation: Department of Medical Oncology, Erasmus MC Cancer Institute, Wytemaweg, Rotterdam, The Netherlands.|Division of Pharmaceutics and Pharmaceutical Chemistry, College of Pharmacy, Ohio State University, Columbus, Ohio, USA.
authors.forename: A
authors.initials: A
authors.lastname: Sparreboom
authors.affiliation: Department of Medical Oncology, Erasmus MC Cancer Institute, Wytemaweg, Rotterdam, The Netherlands.
authors.forename: Rhj
authors.initials: R
authors.lastname: Mathijssen
authors.affiliation: Division of Pharmaceutics and Pharmaceutical Chemistry, College of Pharmacy, Ohio State University, Columbus, Ohio, USA.
authors.forename: S D
authors.initials: SD
authors.lastname: Baker
mesh_terms: D000368:Aged; D000818:Animals; D001692:Biological Transport / Q000187:drug effects; D004285:Dogs; D005260:Female; D020719:Glucuronides / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000494:pharmacology*; D057809:HEK293 Cells; D022781:Hepatocytes / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D027381:Liver-Specific Organic Anion Transporter 1 / Q000378:metabolism*; D061985:Madin Darby Canine Kidney Cells; D008297:Male; D018345:Mice, Knockout; D008875:Middle Aged; D000089762:Multidrug Resistance-Associated Protein 2; D009536:Niacinamide / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000493:pharmacokinetics / Q000494:pharmacology; D029362:Organic Anion Transporters, Sodium-Independent / Q000378:metabolism; D010671:Phenylurea Compounds / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000494:pharmacology*; D012293:Rifampin / Q000494:pharmacology; D000077157:Sorafenib
chemical_list: C000715087:ABCC2 protein, human; D020719:Glucuronides; D027381:Liver-Specific Organic Anion Transporter 1; D000089762:Multidrug Resistance-Associated Protein 2; D029362:Organic Anion Transporters, Sodium-Independent; D010671:Phenylurea Compounds; C503999:SLCO1B1 protein, human; C498887:Slco1b2 protein, mouse; D009536:Niacinamide; D000077157:Sorafenib; D012293:Rifampin