Distribution, metabolism, and excretion of [C] purinostat mesylate, a novel selective HDAC I/IIb inhibitor, in rats analyzed by high-performance liquid chromatography coupled with LTQ orbitrap mass spectrometry/radioactivity monitoring.

in Journal of pharmaceutical and biomedical analysis by Ziyan Ma, Minghai Tang, Linyu Yang, Lijuan Chen

TLDR

  • This study explored the pharmacokinetics of Purinostat Mesylate (PM), a novel HDAC inhibitor, in rats, revealing its distribution, elimination, and metabolism properties.

Abstract

Purinostat Mesylate (PM) is a novel and highly efficient selective histone deacetylase (HDAC) I/IIb inhibitor for hematologic tumor treatment that was granted Investigational New Drug (IND) approval for clinical investigation by the National Medical Products Administration and is currently in phase IIb clinical trials for relapsed/refractory diffuse large B-cell lymphoma. In this paper, the excretion, distribution, and metabolism properties of this IND were researched by High-Performance Liquid Chromatography coupled with LTQ Orbitrap Mass Spectrometry/Radioactivity Monitoring (HPLC-LTQ-Orbitrap-MS/RAM) and liquid scintillation counting. Following a single intravenous dose of [C] PM to rats, a total of 98.49 % of the dose was recovered from intact rats within 0-168 h post-dose, with 14.16 % in urine and 83.15 % in feces, most of which was recovered within the first 24 h post-dose. For bile duct cannulated rats, a total of 95.54 % of the dose was recovered, with 62.37 % in bile, 23.37 % in urine and 8.58 % in feces within 0-72 h post-dose, suggesting that [C] PM was excreted mainly into feces via biliary excretion. [C] PM was distributed widely and eliminated rapidly throughout the body, with the lung, liver, kidney and intestine as the main organs. Interestingly, slow elimination was observed in the spleen, which could benefit the functional restoration of the spleen in hematological tumors. In terms of metabolism, [C] PM underwent an extensive metabolic transformation in rats. Fourteen metabolites were tentatively identified, with major phase I metabolic pathways encompassing reduction, N-dealkylation, and oxidative deamination. Concomitantly, the primary phase II metabolic routes involved acetylation and glucuronic acid conjugation. This study was the first comprehensive PM pharmacokinetic study utilizing [C] isotope labeling technology.

Overview

  • The study investigated the excretion, distribution, and metabolism properties of Purinostat Mesylate (PM), a novel HDAC I/IIb inhibitor, in rats.
  • The study aimed to provide a comprehensive understanding of PM pharmacokinetics using [C] isotope labeling technology.
  • The research explored PM's distribution and elimination in different organs, as well as its metabolic transformation pathways.

Comparative Analysis & Findings

  • A total of 98.49% of the [C] PM dose was recovered from intact rats within 0-168h post-dose, with 14.16% in urine and 83.15% in feces.
  • For bile duct cannulated rats, 95.54% of the dose was recovered, with 62.37% in bile, 23.37% in urine, and 8.58% in feces within 0-72h post-dose.
  • PM was distributed widely and eliminated rapidly throughout the body, with the lung, liver, kidney, and intestine being the main organs, but slow elimination was observed in the spleen.

Implications and Future Directions

  • The study's findings suggest that PM may be excreted mainly via biliary excretion, which could be beneficial for patients with impaired renal function.
  • The results highlight the need for further investigation into PM's metabolic pathways and the potential implications for its clinical efficacy and safety.
  • Future studies should explore the efficacy and safety of PM in different patient populations and disease settings, as well as its potential interactions with other therapeutic agents.
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