Abstract
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.
Highlights
A number of histone deacetylase (HDAC) inhibitors have been tested in clinical trials for the treatment of various types of tumors [1,2], neurodegenerative disorders [3], inflammation disorders [4], and cardiovascular disease [5]
In the breast tumor xenograft in mice treated with ZL277, we found ZL277-B(OH)2-452, ZL277-OH-424, and belinostat and its derivatives
The xenograft breast tumor from mice treated with ZL277 showed the accumulation of belinostat and its precursors ZL277-B(OH)2-452 and ZL277-OH-424, with concentrations over 15-fold of that of belinostat found in tumor tissues of mice treated with belinostat
Summary
A number of histone deacetylase (HDAC) inhibitors have been tested in clinical trials for the treatment of various types of tumors [1,2], neurodegenerative disorders [3], inflammation disorders [4], and cardiovascular disease [5]. Belinostat and other HDAC inhibitors have very limited therapeutic outcome for the treatment of nonhematological cancers in completed clinical trials [2]. TThhee pphhaarrmmaaccookkiinneettiiccss ((PPKK)) aanndd mmeettaabboolliissmm ooff bbeelliinnoossttaatt hhaavvee bbeeeenneexxtteennssiivveellyyssttuuddiieedd[[1133––1199]]. It has been rreeppoorrtteedd tthhaattbbeelliinnoossttaattuunnddeerrggooeessrraappididggluluccuuroronnididaatitoionn, ,cacatatlaylyzezdedbybyUUGGT1TA1A1,1-,1-A1A3,3-, -11AA88,,--22BB44,,aanndd--22BB77[[1133,,1144,,1188]]..TThheemmaaiinnmmeettaabboolliiccppaatthhwwaayyooffbbeelliinnoossttaattiisstthhrroouugghhgglluuccuurroonniiddaattiioonn,, mediated primarily by UGT1A1, and the predominant site of belinostat glucuronidation was found at the hydroxyl position, while other minor metabolites are belinostat amide, belinostat acid, methyl belinostat, belinostat glucoside and 3-(anilinosulfonyl)-benzenecarboxylic acid. These metabolites of belinostat are inactive or very weakly active in clonogenic assays.
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