Dataset Information

Metabolism and Pharmacokinetic Study of the Boron-Containing Prodrug of Belinostat (ZL277), a Pan HDAC Inhibitor with Enhanced Bioavailability.

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.

SUBMITTER: Zhang C

PROVIDER: S-EPMC6958523 | biostudies-literature | 2019 Dec

REPOSITORIES: biostudies-literature

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Metabolism and Pharmacokinetic Study of the Boron-Containing Prodrug of Belinostat (ZL277), a Pan HDAC Inhibitor with Enhanced Bioavailability.

Zhang Changde C Guo Shanchun S Zhong Qiu Q Zhang Qiang Q Hossain Ahamed A Zheng Shilong S Wang Guangdi G

Pharmaceuticals (Basel, Switzerland) 20191208 4

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)<sub>2</sub>-452, the major oxidative metabolite Z ...[more]

PMID: 31817969

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Project description:Pharmacokinetic modeling and simulation is a powerful tool for the prediction of drug concentrations in the absence of analytical techniques that allow for direct quantification. The present study applied this modeling approach to determine active drug release from a nanoparticle prodrug formulation. A comparative pharmacokinetic study of a nanoscale micellar docetaxel (DTX) prodrug, Procet 8, and commercial DTX formulation, Taxotere, was conducted in bile duct cannulated rats. The nanoscale (~40nm) size of the Procet 8 formulation resulted in confinement within the plasma space and high prodrug plasma concentrations. Ex vivo prodrug hydrolysis during plasma sample preparation resulted in unacceptable error that precluded direct measurement of DTX concentrations. Pharmacokinetic modeling of Taxotere and Procet 8 plasma concentrations, and their associated biliary metabolites, allowed for prediction of the DTX concentration profile and DTX bioavailability, and thereby evaluation of Procet 8 metabolism. Procet 8 plasma decay and in vitro plasma hydrolytic rates were identical, suggesting that systemic clearance of the prodrug was primarily metabolic. The Procet 8 and Taxotere plasma profiles, and associated docetaxel hydroxy-tert-butyl carbamate (HDTX) metabolite biliary excretion, were best fit by a two compartment model, with both linear and non-linear DTX clearance, and first order Procet 8 hydrolysis. The model estimated HDTX clearance rate agreed with in vitro literature values, supporting the predictability of the proposed model. Model simulation at the 10mg DTX equivalent/kg dose level predicted DTX formation rate-limited kinetics and a peak plasma DTX concentration of 39ng/mL at 4h for Procet 8, in comparison to 2826ng/mL for Taxotere. As a result of nonlinear DTX clearance, the DTX AUCinf for the Procet 8 formulation was predicted to be 2.6 times lower than Taxotere (775 vs. 2017h×ng/mL, respectively), resulting in an absolute bioavailability estimate of 38%. As DTX clearance in man is considered linear, this low bioavailability is likely species-dependent. These data support the use of pharmacokinetic modeling and simulation in cases of complex formulations, where analytical methods for direct measurement of free (released) drug concentrations are unavailable. Uses of such models may include interpretation of preclinical toxicology studies, selection of first in man dosing regimens, and PK/PD model development.

Dataset Information

Metabolism and Pharmacokinetic Study of the Boron-Containing Prodrug of Belinostat (ZL277), a Pan HDAC Inhibitor with Enhanced Bioavailability.

Publications

Metabolism and Pharmacokinetic Study of the Boron-Containing Prodrug of Belinostat (ZL277), a Pan HDAC Inhibitor with Enhanced Bioavailability.

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