title: Sorafenib metabolism, transport, and enterohepatic recycling: physiologically based modeling and simulation in mice.
abstract: This study used uncertainty and sensitivity analysis to evaluate a physiologically based pharmacokinetic (PBPK) model of the complex mechanisms of sorafenib and its two main metabolites, sorafenib glucuronide and sorafenib N-oxide in mice.
  
  
  
  A PBPK model for sorafenib and its two main metabolites was developed to explain disposition in mice. It included relevant influx (Oatp) and efflux (Abcc2 and Abcc3) transporters, hepatic metabolic enzymes (CYP3A4 and UGT1A9), and intestinal β-glucuronidase. Parameterization of drug-specific processes was based on in vitro, ex vivo, and in silico data along with plasma and liver pharmacokinetic data from single and multiple transporter knockout mice.
  
  
  
  Uncertainty analysis demonstrated that the model structure and parameter values could explain the observed variability in the pharmacokinetic data. Global sensitivity analysis demonstrated the global effects of metabolizing enzymes on sorafenib and metabolite disposition and the local effects of transporters on their respective substrate exposures. In addition, through hypothesis testing, the model supported that the influx transporter Oatp is a weak substrate for sorafenib and a strong substrate for sorafenib glucuronide and that the efflux transporter Abcc2 is not the only transporter affected in the Abcc2 knockout mouse.
  
  
  
  Translation of the mouse model to humans for the purpose of explaining exceptionally high human pharmacokinetic variability and its relationship with exposure-dependent dose-limiting toxicities will require delineation of the importance of these processes on disposition.
authors.affiliation: School of Pharmacy, University of Waterloo, Waterloo, ON, Canada.
authors.forename: Andrea N
authors.initials: AN
authors.lastname: Edginton
authors.affiliation: Department of Pharmaceutical Sciences, St. Jude Children's Research Hospital, 262 Danny Thomas Place, Memphis, TN, 38105, USA.
authors.forename: Eric I
authors.initials: EI
authors.lastname: Zimmerman
authors.affiliation: Department of Pharmaceutical Sciences, St. Jude Children's Research Hospital, 262 Danny Thomas Place, Memphis, TN, 38105, USA.
authors.forename: Aksana
authors.initials: A
authors.lastname: Vasilyeva
authors.affiliation: Department of Pharmaceutical Sciences, St. Jude Children's Research Hospital, 262 Danny Thomas Place, Memphis, TN, 38105, USA.|Division of Pharmaceutics, College of Pharmacy and Comprehensive Cancer Center, The Ohio State University, Columbus, OH, USA.
authors.forename: Sharyn D
authors.initials: SD
authors.lastname: Baker
authors.affiliation: Department of Pharmaceutical Sciences, St. Jude Children's Research Hospital, 262 Danny Thomas Place, Memphis, TN, 38105, USA. carl.panetta@stjude.org.
authors.forename: John C
authors.initials: JC
authors.lastname: Panetta
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000097:blood / Q000378:metabolism / Q000493:pharmacokinetics*; D003198:Computer Simulation; D051544:Cytochrome P-450 CYP3A / Q000235:genetics / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D014453:Glucuronosyltransferase / Q000235:genetics / Q000378:metabolism; D008099:Liver / Q000201:enzymology / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D008954:Models, Biological; D000089762:Multidrug Resistance-Associated Protein 2; D027425:ATP-Binding Cassette, Sub-Family C Proteins / Q000235:genetics / Q000378:metabolism; D009536:Niacinamide / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000097:blood / Q000378:metabolism / Q000493:pharmacokinetics; D010671:Phenylurea Compounds / Q000008:administration & dosage / Q000097:blood / Q000378:metabolism / Q000493:pharmacokinetics*; D000077157:Sorafenib; D014018:Tissue Distribution; D000090264:UDP-Glucuronosyltransferase 1A9
chemical_list: D000970:Antineoplastic Agents; D051544:Cytochrome P-450 CYP3A; D014453:Glucuronosyltransferase; D000089762:Multidrug Resistance-Associated Protein 2; D027425:ATP-Binding Cassette, Sub-Family C Proteins; D009536:Niacinamide; D010671:Phenylurea Compounds; D000077157:Sorafenib; D000090264:UDP-Glucuronosyltransferase 1A9; C000715087:ABCC2 protein, human; C000715591:UGT1A9 protein, human; C000715592:Ugt1a9 protein, mouse; C114462:multidrug resistance-associated protein 3; C000592551:cytochrome P450 3A4, mouse
keywords: Efflux transporters; Influx transporters; Physiologically based pharmacokinetics; Sensitivity analysis; Sorafenib