Distribution, metabolism, and excretion of [14C] 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

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 [¹⁴C] 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 [¹⁴C] PM was excreted mainly into feces via biliary excretion. [¹⁴C] 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, [¹⁴C] 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 [¹⁴C] isotope labeling technology.