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Updated: Feb 28, 2026
Simultaneous Measurement of HDAC1 and HDAC6 Activity in HeLa Cells Using UHPLC-MS
Published on: August 10, 2017
Intracellular vorinostat accumulation and its relationship to histone deacetylase activity in soft tissue sarcoma
Jürgen Burhenne1, Lu Liu2, Christoph E Heilig3
1Department of Clinical Pharmacology and Pharmacoepidemiology, Heidelberg University Hospital, Im Neuenheimer Feld 410, 69120, Heidelberg, Germany. juergen.burhenne@med.uni-heidelberg.de.
Purpose:
In the regulation of chromatin-structure and histone function, histone deacetylases (HDACs) are key enzymes and thus modulators of epigenetic regulation and gene expression. Accesses of the HDAC inhibitor vorinostat to intracellular compartments are essential to exert epigenetic effects.
Methods:
In ten sarcoma patients receiving oral Zolinza (400 mg qd) vorinostat concentrations in plasma and peripheral blood mononuclear cells (PBMCs) were quantified using validated LC/MS/MS assays to determine intracellular and extracellular pharmacokinetic data. Cellular HDAC activity was evaluated using a fluorogenic assay. Concentration-response relationships were established between intracellular and extracellular vorinostat concentrations and HDAC inhibition in PBMCs.
Results:
Pharmacokinetics of vorinostat and its two main inactive metabolites were determined over 8 h in plasma and PBMCs. Steady state AUCs (±SD) and T1/2 (±SD) were calculated to 4.61 ± 0.87 h µM and 1.73 ± 0.69 h (plasma) and 15.2 ± 9.03 h µM and 5.30 ± 4.27 h (PBMCs). Intracellular accumulation of vorinostat was determined together with prolonged vorinostat elimination in PBMCs. Cellular HDAC inhibition increased parallel with vorinostat concentrations in plasma and PBMCs. For effective inhibition of cellular HDACs (IC50) vorinostat concentrations of 0.05 µM in plasma and 0.17 µM in PBMCs were necessary.
Conclusion:
HDAC inhibition closely followed intracellular vorinostat concentrations and was short-lasting, which may contribute to the limited efficacy seen with vorinostat in solid tumors so far.
Insights
Vorinostat, an HDAC inhibitor, accumulates intracellularly in patients, but its epigenetic effects are short-lived. This may explain its limited efficacy in solid tumors, despite effective HDAC inhibition.
Area of Science:
- Pharmacology
- Epigenetics
- Oncology
Background:
- Histone deacetylases (HDACs) regulate chromatin structure and gene expression.
- HDAC inhibitors like vorinostat are crucial for epigenetic modulation.
- Intracellular access of vorinostat is key to its epigenetic effects.
Purpose of the Study:
- To quantify vorinostat concentrations in plasma and PBMCs.
- To determine intracellular and extracellular pharmacokinetic data.
- To establish concentration-response relationships between vorinostat levels and HDAC inhibition.
Main Methods:
- LC/MS/MS assays for vorinostat quantification in plasma and PBMCs.
- Fluorogenic assay for cellular HDAC activity evaluation.
- Pharmacokinetic analysis including AUC and T1/2 determination.
Main Results:
- Vorinostat showed intracellular accumulation and prolonged elimination in PBMCs.
- HDAC inhibition correlated with intracellular and plasma vorinostat concentrations.
- Effective HDAC inhibition required specific vorinostat concentrations in plasma and PBMCs.
Conclusions:
- HDAC inhibition closely mirrors intracellular vorinostat levels.
- The short-lasting nature of HDAC inhibition may limit vorinostat's efficacy in solid tumors.
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