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Article Abstract
Background: Givinostat, a potent histone deacetylase (HDAC) inhibitor, is promising for the treatment of relapsed leukemia and myeloma.
Purpose: This study aimed to develop and verify a quick assay for the measurement of givinostat concentration using ultra-performance liquid chromatography tandem mass spectrometry (UPLC-MS/MS) with eliglustat as the internal standard (IS), establishing a basic pharmacokinetic profile for its pre-clinical application and metabolic stability in vitro.
Methods: Sample preparation was performed via protein precipitation using acetonitrile. The analyte (givinostat) and IS were gradient eluted on a Waters ACQUITY UPLC BEH C18 column (1.7 μm, 2.1 × 50 mm) with 0.1% formic acid (A) and acetonitrile (B) as the mobile-phase system. The multiple reaction monitoring (MRM) in positive ion mode was used to detect the mass transition pairs for givinostat and IS as follows: 422.01→186.11 for givinostat, and 405.40→84.10 for IS, respectively.
Results: In the bioanalytical method, good linearity was observed between 2 and 4000 ng/mL ( =0.998). The intra- and inter-day precisions (RSD%) were lower than 15%, with an accuracy (RE%) of 95.8%-108.6%. The recovery exceeded 90%, and the matrix effect was within the range of 98.2%-107.6%. Additionally, this method was successful in evaluating pharmacokinetics in rats after an oral dose of 10 mg/kg givinostat. Finally, in vitro results showed that givinostat had a slow intrinsic clearance (CLint) value of 14.92 μL/min/mg protein with a half-life (t) value of 92.87 min.
Conclusion: Givinostat was rapidly absorbed and cleared slowly in vivo, and it was confirmed by in vitro experiments. This study provides a potential reference for givinostat in clinical studies.
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| http://www.ncbi.nlm.nih.gov/pmc/articles/PMC11742092 | PMC |
| http://dx.doi.org/10.2147/DDDT.S497308 | DOI Listing |
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