Glucuronidation by UGT1A1 Is the Dominant Pathway of the Metabolic Disposition of Belinostat in Liver Cancer Patients

PLoS ONE

Volumn 8, Issue 1, 2013, Pages

  Wang, Ling Zhi ^a,b   Ramírez, Jacqueline ^c   Yeo, Winnie ^d   Chan, Mei Yi Michelle ^b   Thuya, Win Lwin ^a   Lau, Jie Ying Amelia ^a   Wan, Seow Ching ^a   Wong, Andrea Li Ann ^e   Zee, Ying Kiat ^e   Lim, Robert ^e   Lee, Soo Chin ^a,e   Ho, Paul C ^b   Lee, How Sung ^b   Chan, Anthony ^d   Ansher, Sherry ^f   Ratain, Mark J ^c   Goh, Boon Cher ^a,b,e  

^a NATIONAL UNIVERSITY OF SINGAPORE   (Singapore)

^b NATIONAL UNIVERSITY OF SINGAPORE   (Singapore)

^c UNIVERSITY OF CHICAGO   (United States)

^d CHINESE UNIVERSITY OF HONG KONG   (Hong Kong)

^e NATIONAL UNIVERSITY HEALTH SYSTEM   (Singapore)

^f Cancer Therapy Evaluation Program   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

BELINOSTAT; BELINOSTAT ACID; BELINOSTAT AMIDE; BELINOSTAT GLUCOSIDE; BELINOSTAT GLUCURONIDE; DRUG METABOLITE; GLUCURONOSYLTRANSFERASE 1A1; METHYLBELINOSTAT; UNCLASSIFIED DRUG;

AREA UNDER THE CURVE; ARTICLE; CLINICAL ARTICLE; CONCENTRATION RESPONSE; CONTROLLED STUDY; DOSE RESPONSE; DRUG CLEARANCE; DRUG CYTOTOXICITY; DRUG DETERMINATION; DRUG DOSE ESCALATION; DRUG EFFECT; DRUG HALF LIFE; DRUG MEGADOSE; DRUG METABOLISM; DRUG POTENCY; DRUG STRUCTURE; GENE EXPRESSION; GENE FREQUENCY; GENE IDENTIFICATION; GENOTYPING TECHNIQUE; GLUCURONIDATION; HUMAN; HUMAN CELL; LIGHT ABSORPTION; LIVER CANCER; LIVER MICROSOME; MASS SPECTROMETRY; MAXIMUM PLASMA CONCENTRATION; MULTICENTER STUDY; PHASE 1 CLINICAL TRIAL; TIME TO MAXIMUM PLASMA CONCENTRATION; UDP GLUCURONOSYLTRANSFERASE 1A1 GENE; WILD TYPE;

ANTINEOPLASTIC AGENTS; CARCINOMA, HEPATOCELLULAR; DRUG STABILITY; GENE EXPRESSION; GENOTYPE; GLUCURONOSYLTRANSFERASE; HISTONE DEACETYLASE INHIBITORS; HUMANS; HYDROGEN-ION CONCENTRATION; HYDROXAMIC ACIDS; KINETICS; LIVER NEOPLASMS; METABOLIC NETWORKS AND PATHWAYS; METABOLOME; MICROSOMES, LIVER; SUBSTRATE SPECIFICITY; SULFONAMIDES;

EID: 84873862018     PISSN: None     EISSN: 19326203     Source Type: Journal    
DOI: 10.1371/journal.pone.0054522     Document Type: Article

References (37)

1. Marks PA, Richon VM, Miller T, Kelly WK, (2004) Histone deacetylase inhibitors. Adv Cancer Res 91: 137-168.
2. Gray SG, Qian CN, Furge K, Guo X, The BT, (2004) Microarray profiling of the effects of histone deacetylase inhibitors on gene expression in cancer cell lines. Int J Oncol 24: 773-795.
3. Mitsiades CS, Mitsiades NS, Mcmullan CJ, Poulaki V, Shringarpure R, et al. (2004) Transcriptional signature of histone deacetylase inhibition in multiple myeloma: biological and clinical implications. Proc Natl Acad Sci 101: 540-545.
4. Peart MJ, Smyth GK, van Laar RK, Bowtell DD, Richon VM, et al. (2005) Identification and functional significance of genes regulated by structurally different histone deacetylase inhibitors. Proc Natl Acad Sci 102: 3697-3702.
5. Tanji N, Ozawa A, Kikugawa T, Miura N, Sasaki T, et al. (2011) Potential of histone deacetylase inhibitors for bladder cancer treatment. Expert Rev Anticancer Ther 1: 959-965.
6. Bapat SA, (2010) Modulation of gene expression in ovarian cancer by active and repressive histone marks. Epigenomics 2: 39-51.
7. Piekarz RL, Bates SE, (2009) Epigenetic modifiers: basic understanding and clinical development. Clin Cancer Res 15: 3918-3926.
8. Piekarz RL, Frye R, Prince HM, Kirschbaum MH, Zain J, et al. (2011) Phase 2 trial of romidepsin in patients with peripheral T-cell lymphoma. Blood. 117: 5827-5834.
9. Mann BS, Johnson JR, Cohen MH, Justice R, Pazdur R, (2007) FDA Approval Summary: Vorinostat for Treatment of Advanced Primary Cutaneous T-Cell Lymphoma. The Oncologist. 12: 1247-1252.
10. Howman RA, Prince HM, (2011) New drug therapies in peripheral T-cell lymphoma. Expert Rev Anticancer Ther 11: 457-472.
11. Steele NL, Plumb JA, Vidal L, Tjornelund J, Knoblauch P, et al. (2008) A Phase 1 Pharmacokinetic and Pharmacodynamic Study of the Histone Deacetylase Inhibitor Belinostat in Patients with Advanced Solid Tumors. Clin Cancer Res 14: 804-810.
12. Na YS, Jung KA, Kim SM, Hong YS, Ryu MH, et al. (2011) The histone deacetylase inhibitor PXD101 increases the efficacy of irinotecan in in vitro and in vivo colon cancer models. Cancer Chemother Pharmacol 68: 389-398.
13. Ramalingam SS, Belani CP, Ruel C, Frankel P, Gitlitz B, et al. (2009) Phase II study of belinostat (PXD101), a histone deacetylase inhibitor, for second line therapy of advanced malignant pleural mesothelioma. J Thorac Oncol 4: 97-101.
14. Tumber A, Collins LS, Petersen KD, Thougaard A, Dejligbjerg M, et al. (2007) The histone deacetylase inhibitor PXD101 synergises with 5-fluorouracil to inhibit colon cancer cell growth in vitro and in vivo. Cancer Chemother Pharmacol. 60: 275-283.
15. Dai Y, Chen S, Wang L, Pei XY, Kramer LB, et al. (2011) Bortezomib interacts synergistically with belinostat in human acute myeloid leukaemia and acute lymphoblastic leukaemia cells in association with perturbation in NF-κB and Bim. Br J Haematol. 152(2): 222-235.
16. Giaccone G, Rajan A, Berman A, Kelly RJ, Szabo E, et al. (2011) Phase II study of belinostat in patients with recurrent or refractory advanced thymic epithelial tumors. J Clin Oncol. 29: 2052-2059.
17. Cashen A, Juckett M, Jumonville A, Litzow M, Flynn PJ, et al. (2012) Phase II study of the histone deacetylase inhibitor belinostat (PXD101) for the treatment of myelodysplastic syndrome (MDS). Ann Hematol 91(1): 33-38.
18. Mackay HJ, Hirte H, Colgan T, Covens A, MacAlpine K, et al. (2010) Phase II trial of the histone deacetylase inhibitor belinostat in women with platinum resistant epithelial ovarian cancer and micropapillary (LMP) ovarian tumours. Eur J Cancer 46: 1573-1579.
19. Kang SP, Ramirez J, House L, Zhang W, Mirkov S, et al. (2010) A pharmacogenetic study of vorinostat glucuronidation. Pharmacogenet. Genomics 20: 638-641.
20. Wong NS, Seah EZ, Wang LZ, Yeo WL, Yap HL, et al. (2011) Impact of UDP-gluconoryltransferase 2B17 genotype on vorinostat metabolism and clinical outcomes in Asian women with breast cancer. Pharmacogenet. Genomics 21(11): 760-768.
21. Clive S, Woo MM, Stewart M, Nydam T, Hirawat S, et al. (2009) Elucidation of the metabolic and elimination pathways of panobinostat (LBH589) using [14C]-panobinostat. J Clin Oncol 27: 15s.
22. Shiraga T, Tozuka Z, Ishimura R, Kawamura A, Kagayama A, (2005) Identification of cytochrome P450 enzymes involved in the metabolism of FK228, a potent histone deacetylase inhibitor, in human liver microsomes. Biol Pharm Bull. 28: 124-129.
23. Balliet RM, Chen G, Gallagher CJ, Dellinger RW, Sun D, et al. (2009) Characterization of UGTs active against SAHA and association between SAHA glucuronidation activity phenotype with UGT genotype. Cancer Res. 69: 2981-2989.
24. Wang LZ, Chan D, Yeo W, Wan SC, Chan S, et al. (2010) A sensitive and specific liquid chromatography-tandem mass spectrometric method for determination of belinostat in plasma from liver cancer patients. J Chromatogr B Biomed Sci Appl. 878: 2409-2414.
25. Iyer L, Hall D, Das S, Mortell MA, Ramirez J, et al. (1999) Phenotype-genotype correlation of in vitro SN-38 (active metabolite of irinotecan) and bilirubin glucuronidation in human liver tissue with UGT1A1 promoter polymorphism. Clin Pharmacol Ther 65: 576-582.
26. Yoder Graber AL, Ramirez J, Innocenti F, Ratain MJ, (2007) UGT1A1*28 genotype affects the in-vitro glucuronidation of thyroxine in human livers. Pharmacogenet Genomics 17: 619-627.
27. Innocenti F, Liu W, Chen P, Desai AA, Das S, et al. (2005) Haplotypes of variants in the UDP-glucuronosyltransferase 1A9 and 1A1 genes. Pharmacogenet Genomics 15: 295-301.
28. Babu SR, Lakshmi VM, Hsu FF, Zenser TV, Davis BB, et al. (1995) Glucuronidation of N-hydroxy metabolits of N-acetylbenzidine. Carcinogenesis. 16: 3069-3074.
29. Marco C, Vijaya ML, Nikhil B, Davis BB, Owens IS, et al. (1999) Glucuronidation of benzidine and its metabolites by cDNA-expressed human UDP-glucuronosyltransferases and pH stability of glucuronides. Carcinogenesis. 20: 1963-1969.
30. Du LH, Musson DG, Wang AQ, (2005) High turbulence liquid chromatography online extraction and tandem mass spectrometry for the simultaneous determination of suberoylanilide hydroxamic acid and its two metabolites in human serum. Rapid Commun Mass Spectrom 19: 1779-1787.
31. Izukawa T, Nakajima M, Fujiwara R, Yamanaka H, Fukami T, et al. (2009) Quantitative analysis of UDP-glucuronosyltransferase (UGT) 1A and UGT2B expression levels in human livers. Drug Metab Dispos. 37: 1759-1768.
32. Strassburg CP, Manns MP, Tukey RH, (1998) Expression of the UDP-glucuronosyltransferase 1A locus in human colon. Identification and characterization of the novel extrahepatic UGT1A8. J Biol Chem. 273: 8719-8726.
33. Yeo W, Chung HC, Chan SL, Wang LZ, Lim R, et al. (2012) Epigenetic Therapy Using Belinostat for Patients With Unresectable Hepatocellular Carcinoma: A Multicenter Phase I/II Study With Biomarker and Pharmacokinetic Analysis of Tumors From Patients in the Mayo Phase II Consortium and the Cancer Therapeutics Research Group. J Clin Oncol. 30: 3361-3367.
34. Bosma PJ, Chowdhury JR, Bakker C, Gantla S, de Boer A, et al. (1995) The genetic basis of the reduced expression of bilirubin UDP-glucuronosyltransferase 1 in Gilbert's syndrome. N Engl J Med 333: 1171-1175.
35. Innocenti F, Undevia SD, Iyer L, Chen PX, Das S, et al. (2004) Genetic variants in the UDP-glucuronosyltransferase 1A1 gene predict the risk of severe neutropenia of irinotecan. J Clin Oncol. 22: 1382-1388.
36. Hoskins JM, Goldberg RM, Qu P, Ibrahim JG, McLeod HL, (2007) UGT1A1*28 genotype and irinotecan-induced neutropenia: dose matters. J Natl Cancer Inst. 99: 1290-1295.
37. Beutler E, Gelbart T, Demina A, (1998) Racial variability in the UDP-glucuronosyltransferase 1 (UGT1A1) promoter: a balanced polymorphism for regulation of bilirubin metabolism? Proc Natl Acad Sci U S A. 95: 8170-8174.