title: Sorafenib hepatobiliary disposition: mechanisms of hepatic uptake and disposition of generated metabolites.
abstract: Sorafenib is an orally active tyrosine kinase inhibitor used in the treatment of renal and hepatocellular carcinoma. This study was designed to establish whether transport proteins are involved in the hepatic uptake of sorafenib and to determine the extent of biliary excretion of sorafenib and its metabolites in human hepatocytes. Initial uptake was assessed in freshly isolated, suspended human hepatocytes in the presence of inhibitors and modulators. [(14)C]Sorafenib (1 µM) uptake at 4°C was reduced by about 61-63% of the uptake at 37°C, suggesting a high degree of passive diffusion. Hepatocyte uptake of [(14)C]sorafenib was not Na(+) dependent or influenced by the organic anion transporter 2 inhibitor ketoprofen. However, initial [(14)C]sorafenib hepatocyte uptake was reduced by 46 and 30% compared with control values in the presence of the organic anion transporting polypeptide inhibitor rifamycin SV and the organic cation transporter (OCT) inhibitor decynium 22, respectively. [(14)C]Sorafenib (0.5-5 µM) uptake was significantly higher in hOCT1-transfected Chinese hamster ovary cells compared with mock cells, and inhibited by the general OCT inhibitor, 1-methyl-4-phenylpryidinium. OCT1-mediated uptake was saturable with a Michaelis-Menten constant of 3.80 ± 2.53 µM and a V(max) of 116 ± 42 pmol/mg/min. The biliary excretion index and in vitro biliary clearance of sorafenib (1 µM) in sandwich-cultured human hepatocytes were low (∼11% and 11 ml/min/kg, respectively). Results suggest that sorafenib uptake in human hepatocytes occurs via passive diffusion, by OCT1, and by organic anion transporting polypeptide(s). Sorafenib undergoes modest biliary excretion, predominantly as a glucuronide conjugate(s).
authors.affiliation: Division of Pharmacotherapy and Experimental Therapeutics, UNC Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
authors.forename: Brandon
authors.initials: B
authors.lastname: Swift
authors.forename: Noelia
authors.initials: N
authors.lastname: Nebot
authors.forename: Jin Kyung
authors.initials: JK
authors.lastname: Lee
authors.forename: Tianxiang
authors.initials: T
authors.lastname: Han
authors.forename: William R
authors.initials: WR
authors.lastname: Proctor
authors.forename: Dhiren R
authors.initials: DR
authors.lastname: Thakker
authors.forename: Dieter
authors.initials: D
authors.lastname: Lang
authors.forename: Martin
authors.initials: M
authors.lastname: Radtke
authors.forename: Mark J
authors.initials: MJ
authors.lastname: Gnoth
authors.forename: Kim L R
authors.initials: KL
authors.lastname: Brouwer
mesh_terms: D000328:Adult; D000818:Animals; D016466:CHO Cells; D002478:Cells, Cultured; D006224:Cricetinae; D003412:Cricetulus; D005260:Female; D022781:Hepatocytes / Q000187:drug effects / Q000378:metabolism*; D006801:Humans; D008297:Male; D008875:Middle Aged; D009536:Niacinamide / Q000031:analogs & derivatives* / Q000378:metabolism / Q000494:pharmacology; D010671:Phenylurea Compounds / Q000378:metabolism* / Q000494:pharmacology; D047428:Protein Kinase Inhibitors / Q000378:metabolism* / Q000494:pharmacology; D000077157:Sorafenib
chemical_list: D010671:Phenylurea Compounds; D047428:Protein Kinase Inhibitors; D009536:Niacinamide; D000077157:Sorafenib