Liquid chromatography mass spectrometry determination of mocetinostat (MGCD0103) in rat plasma and its application to a pharmacokinetic study

Abstract

1. Mocetinostat (MGCD0103) is a benzamide histone deacetylase inhibitor undergoing clinical trials for treatment of various cancers including Hodgkin's lymphoma, follicular lymphoma and acute myelogenous leukemia. A sensitive and selective liquid chromatography mass spectrometry method for determination of MGCD0103 in rat plasma was developed.

2. After addition of midazolam as internal standard (IS), protein precipitation by acetonitrile was used as sample preparation. Chromatographic separation was achieved on a C18 (2.1 mm × 50 mm, 3.5 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 397 for MGCD0103 and m/z 326 for the IS.

3. Calibration plots were linear over the range of 5–5000 ng/mL for MGCD0103 in rat plasma. Mean recoveries of MGCD0103 in rat plasma were in the range of 89.7–96.1%. RSD of intra-day and inter-day precision were both <11%. The accuracy of the method ranged from 96.5% to 109.7%. The matrix effects for MGCD0103 were between 94.5% and 97.4%.

4. The method was successfully applied to pharmacokinetic study of MGCD0103 after oral (15 mg/kg) and intravenous (3 mg/kg) administration in rats. The bioavailability of MGCD0103 was 29.3% in rats.

• HDAC
• LC-MS
• MGCD0103
• pharmacokinetics
• rat plasma