Metabolism and Pharmacokinetic Study of the Boron-Containing Prodrug of Belinostat (Zl277), a Pan Hdac Inhibitor with Enhanced Bioavailability

Funding Source

National Institute on Minority Health and Health Disparities, National Institutes of Health, National Cancer Institute

Grant Number

2R44CA213462, U54MD007595, 2R44CA213462, U54MD007595


Department of Chemistry

Document Type


Publication Date



ZL277 is a prodrug of belinostat with enhanced bioavailability and efficacy as a pan histone deacetylase (HDAC) inhibitor. In this study, we investigated the metabolism and pharmacokinetics of ZL277 in liver S9 fractions, liver microsomes, liver cytosol, and in mice. Metabolic products were identified and quantified by a combination of liquid chromatography and tandem mass spectrometry. The in vitro metabolic profile of ZL277 includes ZL277-B(OH)2-452, the major oxidative metabolite ZL277-OH-424, the active ingredient belinostat, belinostat amide, belinostat acid, and methylated belinostat in liver S9 fractions. Both ZL277-OH-424 and belinostat underwent further glucuronidation in liver microsome, whereas only ZL277-OH-424, but not belinostat, underwent some level of sulfation in rat liver cytosols. These metabolites were examined in plasma and in a breast tumor model in vivo. They were also examined in urine and feces from mice treated with ZL277. The pharmacokinetic study of ZL277 showed the parameters of active drug belinostat with a half-life (t1/2) of 10.7 h, an area under curve value (AUC) of 1506.9 ng/mL*h, and a maximum plasma concentration (Cmax) of 172 ng/mL, reached 3 h after a single dose of 10 mg/kg. The hydrolysis product of the prodrug, ZL277-B(OH)2-452 showed an AUC of 8306 ng/mL*h and Cmax of 931 ng/mL 3 h after drug administration.


DOI: 10.3390/ph12040180

  • Funding text #1

    Funding: This study was funded by NIH grants U54MD007595 from NIMHD, 2R44CA213462 from NCI, and by Louisiana Cancer Research Consortium.

  • Funding text #2

    Acknowledgments: This study was supported by NIH grants U54MD007595 from NIMHD, 2R44CA213462 from NCI, and by Louisiana Cancer Research Consortium.