title: Glucuronidation by UGT1A1 is the dominant pathway of the metabolic disposition of belinostat in liver cancer patients.
abstract: Belinostat is a hydroxamate class HDAC inhibitor that has demonstrated activity in peripheral T-cell lymphoma and is undergoing clinical trials for non-hematologic malignancies. We studied the pharmacokinetics of belinostat in hepatocellular carcinoma patients to determine the main pathway of metabolism of belinostat. The pharmacokinetics of belinostat in liver cancer patients were characterized by rapid plasma clearance of belinostat with extensive metabolism with more than 4-fold greater relative systemic exposure of major metabolite, belinostat glucuronide than that of belinostat. There was significant interindividual variability of belinostat glucuronidation. The major pathway of metabolism involves UGT1A1-mediated glucuronidation and a good correlation has been identified between belinostat glucuronide formation and glucuronidation of known UGT1A1 substrates. In addition, liver microsomes harboring UGT1A1*28 alleles have lower glucuronidation activity for belinostat compared to those with wildtype UGT1A1. The main metabolic pathway of belinostat is through glucuronidation mediated primarily by UGT1A1, a highly polymorphic enzyme. The clinical significance of this finding remains to be determined.
  
  
  BACKGROUND
  ClinicalTrials.gov NCT00321594.
authors: Cancer Science Institute of Singapore, National University of Singapore, Singapore, Singapore.
authors: Ling-Zhi
authors: LZ
authors: Wang
authors: Jacqueline
authors: J
authors: Ramírez
authors: Winnie
authors: W
authors: Yeo
authors: Mei-Yi Michelle
authors: MY
authors: Chan
authors: Win-Lwin
authors: WL
authors: Thuya
authors: Jie-Ying Amelia
authors: JY
authors: Lau
authors: Seow-Ching
authors: SC
authors: Wan
authors: Andrea Li-Ann
authors: AL
authors: Wong
authors: Ying-Kiat
authors: YK
authors: Zee
authors: Robert
authors: R
authors: Lim
authors: Soo-Chin
authors: SC
authors: Lee
authors: Paul C
authors: PC
authors: Ho
authors: How-Sung
authors: HS
authors: Lee
authors: Anthony
authors: A
authors: Chan
authors: Sherry
authors: S
authors: Ansher
authors: Mark J
authors: MJ
authors: Ratain
authors: Boon-Cher
authors: BC
authors: Goh
mesh_terms: D000970:Antineoplastic Agents / Q000378:metabolism / Q000493:pharmacokinetics* / Q000633:toxicity; D006528:Carcinoma, Hepatocellular / Q000201:enzymology / Q000235:genetics / Q000378:metabolism*; D004355:Drug Stability; D015870:Gene Expression; D005838:Genotype; D014453:Glucuronosyltransferase / Q000235:genetics / Q000378:metabolism*; D056572:Histone Deacetylase Inhibitors / Q000378:metabolism / Q000493:pharmacokinetics* / Q000633:toxicity; D006801:Humans; D006863:Hydrogen-Ion Concentration; D006877:Hydroxamic Acids / Q000378:metabolism / Q000493:pharmacokinetics* / Q000633:toxicity; D007700:Kinetics; D008113:Liver Neoplasms / Q000201:enzymology / Q000235:genetics / Q000378:metabolism*; D053858:Metabolic Networks and Pathways; D055442:Metabolome; D008862:Microsomes, Liver / Q000378:metabolism; D013379:Substrate Specificity; D013449:Sulfonamides / Q000378:metabolism / Q000493:pharmacokinetics* / Q000633:toxicity; D000099148:UGT1A1 Enzyme
chemical_list: D000970:Antineoplastic Agents; D014453:Glucuronosyltransferase; D056572:Histone Deacetylase Inhibitors; D006877:Hydroxamic Acids; D013449:Sulfonamides; D000099148:UGT1A1 Enzyme; C487081:belinostat
references: Pharmacogenet Genomics. 2005 May;15(5):295-301
references: 15864130
references: Cancer Chemother Pharmacol. 2007 Jul;60(2):275-83
references: 17124594
references: J Chromatogr B Analyt Technol Biomed Life Sci. 2010 Sep 15;878(26):2409-14
references: 20724229
references: Br J Haematol. 2011 Apr;153(2):222-35
references: 21375523
references: Adv Cancer Res. 2004;91:137-68
references: 15327890
references: J Thorac Oncol. 2009 Jan;4(1):97-101
references: 19096314
references: Cancer Chemother Pharmacol. 2011 Aug;68(2):389-98
references: 21046105
references: Pharmacogenet Genomics. 2011 Nov;21(11):760-8
references: 21849928
references: Clin Cancer Res. 2009 Jun 15;15(12):3918-26
references: 19509169
references: Ann Hematol. 2012 Jan;91(1):33-8
references: 21538061
references: J Clin Oncol. 2004 Apr 15;22(8):1382-8
references: 15007088
references: Proc Natl Acad Sci U S A. 2005 Mar 8;102(10):3697-702
references: 15738394
references: Proc Natl Acad Sci U S A. 1998 Jul 7;95(14):8170-4
references: 9653159
references: Blood. 2011 Jun 2;117(22):5827-34
references: 21355097
references: Expert Rev Anticancer Ther. 2011 Jun;11(6):959-65
references: 21707293
references: Cancer Res. 2009 Apr 1;69(7):2981-9
references: 19318555
references: Oncologist. 2007 Oct;12(10):1247-52
references: 17962618
references: Int J Oncol. 2004 Apr;24(4):773-95
references: 15010814
references: Drug Metab Dispos. 2009 Aug;37(8):1759-68
references: 19439486
references: Eur J Cancer. 2010 Jun;46(9):1573-9
references: 20304628
references: Pharmacogenet Genomics. 2010 Oct;20(10):638-41
references: 20729791
references: J Natl Cancer Inst. 2007 Sep 5;99(17):1290-5
references: 17728214
references: N Engl J Med. 1995 Nov 2;333(18):1171-5
references: 7565971
references: Clin Cancer Res. 2008 Feb 1;14(3):804-10
references: 18245542
references: J Clin Oncol. 2011 May 20;29(15):2052-9
references: 21502553
references: J Clin Oncol. 2012 Sep 20;30(27):3361-7
references: 22915658
references: Clin Pharmacol Ther. 1999 May;65(5):576-82
references: 10340924
references: Proc Natl Acad Sci U S A. 2004 Jan 13;101(2):540-5
references: 14695887
references: Biol Pharm Bull. 2005 Jan;28(1):124-9
references: 15635176
references: Pharmacogenet Genomics. 2007 Aug;17(8):619-27
references: 17622938
references: Epigenomics. 2010 Feb;2(1):39-51
references: 22122747
references: J Biol Chem. 1998 Apr 10;273(15):8719-26
references: 9535849
references: Carcinogenesis. 1999 Oct;20(10):1963-9
references: 10506112
references: Rapid Commun Mass Spectrom. 2005;19(13):1779-87
references: 15945019
references: Expert Rev Anticancer Ther. 2011 Mar;11(3):457-72
references: 21417858
references: Carcinogenesis. 1995 Dec;16(12):3069-74
references: 8603487