title: Plasma protein binding of sorafenib, a multi kinase inhibitor: in vitro and in cancer patients.
abstract: Sorafenib is an orally administered multikinase inhibitor that exhibits antiangiogenic and antitumor activity. Few investigators have been able to correlate cumulative sorafenib dose or total exposure to pharmacodynamic effects. This discrepancy may be in part due to poorly understood protein binding characteristics. Since unbound drug concentrations are believed to be more relevant to pharmacological and toxicological responses than total drug, an equilibrium dialysis method using 96-well microdialysis plates was optimized and validated for determining the fraction unbound (F(u)) sorafenib in human plasma and in isolated protein solutions. Unbound sorafenib concentrations were determined in cancer patients receiving the drug orally at a dose of 400 mg and 600 mg twice daily. Sorafenib was extensively bound with mean F(u) value of 0.3% in both non-cancer and cancer patient's plasma. The binding in plasma was concentration independent, indicating a low-affinity, possibly nonspecific and nonsaturable process. In isolated protein solutions, 99.8% and 79.3% of sorafenib was bound to human serum albumin (HSA) (4 g/dL) and α(1)-acid glycoprotein (AAG) (0.1 g/dL) with binding constants of 1.24 × 10(6) M(-1) and 1.40 × 10(5) M(-1), respectively. In cancer patients receiving sorafenib, unbound sorafenib was not correlated with patient characteristics or laboratory values. In conclusion, sorafenib is highly protein bound in human plasma with a higher affinity towards albumin and limited free drug may be partly responsible for its borderline clinical activity.
authors.affiliation: The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Bunting-Blaustein Cancer Research Bldg, Room 1M52, Baltimore, MD 21231-1000, USA.
authors.forename: Maria Cristina
authors.initials: MC
authors.lastname: Villarroel
authors.forename: Keith W
authors.initials: KW
authors.lastname: Pratz
authors.forename: Linping
authors.initials: L
authors.lastname: Xu
authors.forename: John J
authors.initials: JJ
authors.lastname: Wright
authors.forename: B Douglas
authors.initials: BD
authors.lastname: Smith
authors.forename: Michelle A
authors.initials: MA
authors.lastname: Rudek
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000970:Antineoplastic Agents / Q000097:blood / Q000494:pharmacology*; D001798:Blood Proteins / Q000378:metabolism*; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D009369:Neoplasms / Q000188:drug therapy / Q000378:metabolism; D009536:Niacinamide / Q000031:analogs & derivatives* / Q000097:blood / Q000494:pharmacology; D010671:Phenylurea Compounds / Q000097:blood / Q000494:pharmacology*; D011485:Protein Binding; D047428:Protein Kinase Inhibitors / Q000097:blood / Q000494:pharmacology*; D000077157:Sorafenib
chemical_list: D000970:Antineoplastic Agents; D001798:Blood Proteins; D010671:Phenylurea Compounds; D047428:Protein Kinase Inhibitors; D009536:Niacinamide; D000077157:Sorafenib
references.citation: Clin Cancer Res. 2005 Aug 1;11(15):5472-80
references.pmid: 16061863
references.citation: Nat Rev Drug Discov. 2006 Oct;5(10):835-44
references.pmid: 17016424
references.citation: Ann Oncol. 2005 Oct;16(10):1688-94
references.pmid: 16006586
references.citation: Clin Pharmacol Ther. 1982 Sep;32(3):295-302
references.pmid: 7105620
references.citation: Cancer Chemother Pharmacol. 2006 May;57(5):685-92
references.pmid: 16133532
references.citation: Clin Pharmacokinet. 1996 Jun;30(6):445-62
references.pmid: 8792057
references.citation: J Chromatogr B Analyt Technol Biomed Life Sci. 2010 Nov 1;878(29):3033-8
references.pmid: 20870468
references.citation: Scand J Clin Lab Invest. 1968;22(3):211-6
references.pmid: 5710448
references.citation: Br J Cancer. 2005 May 23;92(10):1855-61
references.pmid: 15870716
references.citation: J Chromatogr B Analyt Technol Biomed Life Sci. 2007 Feb 1;846(1-2):1-7
references.pmid: 16798122
references.citation: J Clin Oncol. 2005 Feb 10;23(5):965-72
references.pmid: 15613696
references.citation: Br J Clin Pharmacol. 2011 Aug;72(2):294-305
references.pmid: 21392074
references.citation: Leukemia. 2010 Aug;24(8):1437-44
references.pmid: 20535150
references.citation: Pharm Res. 2011 Dec;28(12):3199-207
references.pmid: 21691893
references.citation: Clin Pharmacokinet. 1992 Dec;23(6):449-68
references.pmid: 1458763