Abstract
A simple, specific and reproducible high-performance liquid chromatography (HPLC) assay method has been developed and validated for the estimation of vorinostat in rat plasma. The bioanalytical procedure involves extraction of vorinostat and phenacetin (internal standard, IS) from rat plasma with simple liquid-liquid extraction process. The chromatographic analysis was performed on a Waters Alliance system using a gradient mobile phase conditions at a flow rate of 1.0 mL/min and Symmetry Shield C18 column maintained at 35 ± 1°C. The eluate was monitored using an UV detector set at 245 nm. Vorinostat and IS eluted at 5.3 and 6.3 min, respectively and the total run time was 10 min. Method validation was performed as per FDA guidelines and the results met the acceptance criteria. The calibration curve was linear over a concentration range of 255-5566 ng/mL (r2 = 0.995). The intra- and inter-day precisions were in the range of 2.60-7.93 and 3.99-8.64%, respectively. The validated HPLC method was successfully applied to a pharmacokinetic study in rats.
Highlights
Histone deacetylases (HDAC) are a family of enzymes that play an important role in regulation of gene transcription
Vorinostat (Figure 1, CAS no: 149647-78-9) or suberanilohydroxamic acid (SAHA) is a novel and first HDAC inhibitor approved by US FDA for treatment of cutaneous T cell lymphoma (CTCL) in 2006
We report the development and validation of a simple, specific and reproducible high-performance liquid chromatography (HPLC) method for quantitation of vorinostat in rat plasma
Summary
Histone deacetylases (HDAC) are a family of enzymes that play an important role in regulation of gene transcription. HDAC inhibitors selectively induce cellular differentiation, growth arrest (including drug resistant subtypes) and apoptosis in a broad spectrum of tumor cells. Vorinostat demonstrated activity in murine xenograft models and it was additive or synergistic when combined with chemotherapy drugs in induction of differentiation and apoptosis of various cancer cell lines [5]. It is available as 100 mg capsules. Cytochrome P 450 enzymes has no role in vorinostat metabolism. Both metabolites (vorinostat-O-glucuronide and 4-anilino-4-oxobutanoic acid) are pharmacologically inactive and at steady state the exposure in humans was 4- and 13-fold, respectively higher than vorinostat. The most drug-related adverse events are diarrhea, fatigue, nausea and anorexia [6]
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