Determination of CUDC-101 in rat plasma by liquid chromatography mass spectrometry and its application to a pharmacokinetic study.

CUDC-101 is a multi-targeted, small-molecule inhibitor of histone deacetylase (HDAC), epidermal growth factor receptor tyrosine kinase (EGFR/ErbB1), and human epidermal growth factor receptor 2 tyrosine kinase (HER2/neu or ErbB2) with potential antineoplastic activity. A sensitive and selective liquid chromatography mass spectrometry method for determination of CUDC-101 in rat plasma was developed. After addition of carbamazepine as internal standard (IS), protein precipitation by acetonitrile-methanol (9:1, v/v) was used as sample preparation. Chromatographic separation was achieved on a Zorbax SB-C18 (2.1 mm × 150 mm, 5 μm) column with acetonitrile-0.1% formic acid in water as mobile phase with gradient elution. An electrospray ionization source was applied and operated in positive ion mode; selective ion monitoring (SIM) mode was used for quantification using target fragment ions m/z 435 for CUDC-101 and m/z 237 for the IS. Calibration plots were linear over the range of 5-2000 ng/mL for CUDC-101 in rat plasma. Mean recoveries of CUDC-101 in rat plasma were in the range of 84.0-90.5%. RSD of intra-day and inter-day precision were both <14%. The method was successfully applied to pharmacokinetic study of CUDC-101 after intravenous administration of single dosage 5 mg/kg in rats.