title: Pharmacokinetic study of conventional sorafenib chemoembolization in a rabbit VX2 liver tumor model.
abstract: OBJECTIVE
  Use of oral sorafenib, an antiangiogenic chemotherapeutic agent for hepatocellular carcinoma (HCC), is limited by an unfavorable side effect profile. Transarterial chemoembolization (TACE) employs targeted intravascular drug administration, and has potential as a novel sorafenib delivery method to increase tumoral concentrations and reduce systemic levels. This study aimed to discern the pharmacokinetics of sorafenib TACE in a rabbit VX2 liver tumor model.
  
  
  METHODS
  A 3 mg/kg dose of sorafenib ethiodized oil emulsion was delivered via an arterial catheter to VX2 liver tumors in seven New Zealand white rabbits. Following TACE, serum sorafenib levels were measured at days 0, 1, 2, 3, 7, 10, and 14 until the time of sacrifice, after which rabbit livers were harvested for analysis of sorafenib concentrations within treated tumors and normal liver. Liquid chromatography tandem mass spectrometry was used for drug quantification.
  
  
  RESULTS
  Sorafenib uptake within liver tumor and nontumorous liver tissue peaked at mean 3.53 and 0.75 μg/mL, respectively, immediately post-procedure (5:1 tumor to normal tissue drug uptake ratio), before decreasing with a 10-18 hour half-life. Serum sorafenib levels peaked immediately after TACE at a mean value of 58.58 μg/mL before normalizing with a 5.2-hour half-life, suggesting early drug washout from liver into the systemic circulation. Hepatic lab parameters showed transient increase 24 hours post-TACE with subsequent resolution.
  
  
  CONCLUSIONS
  While targeted transarterial delivery of sorafenib ethiodized oil emulsion shows preferential tumor uptake compared to normal liver, systemic washout occurs with a short half-life, resulting in high circulating drug levels.
authors.affiliation: Department of Radiology, University of Illinois College of Medicine, Chicago, Illinois, USA. rgaba@uic.edu.
authors.forename: Ahmad
authors.initials: A
authors.lastname: Parvinian
authors.forename: Leigh C
authors.initials: LC
authors.lastname: Casadaban
authors.forename: Zane Z
authors.initials: ZZ
authors.lastname: Hauck
authors.forename: Richard B
authors.initials: RB
authors.lastname: van Breemen
authors.forename: Ron C
authors.initials: RC
authors.lastname: Gaba
mesh_terms: D020533:Angiogenesis Inhibitors / Q000008:administration & dosage / Q000009:adverse effects / Q000097:blood / Q000493:pharmacokinetics*; D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000009:adverse effects / Q000097:blood / Q000493:pharmacokinetics; D016461:Chemoembolization, Therapeutic / Q000379:methods*; D004195:Disease Models, Animal; D004998:Ethiodized Oil / Q000008:administration & dosage; D005260:Female; D007269:Injections, Intra-Arterial; D008114:Liver Neoplasms, Experimental / Q000097:blood / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology; D008297:Male; D009536:Niacinamide / Q000008:administration & dosage / Q000009:adverse effects / Q000031:analogs & derivatives* / Q000097:blood / Q000493:pharmacokinetics; D010671:Phenylurea Compounds / Q000008:administration & dosage* / Q000009:adverse effects / Q000097:blood / Q000493:pharmacokinetics*; D047428:Protein Kinase Inhibitors / Q000008:administration & dosage / Q000009:adverse effects / Q000097:blood / Q000493:pharmacokinetics; D011817:Rabbits; D000077157:Sorafenib
chemical_list: D020533:Angiogenesis Inhibitors; D000970:Antineoplastic Agents; D010671:Phenylurea Compounds; D047428:Protein Kinase Inhibitors; D009536:Niacinamide; D004998:Ethiodized Oil; D000077157:Sorafenib
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