title: Development and validation of high-performance liquid chromatography-tandem mass spectrometry assay for 6-(3-benzoyl-ureido)-hexanoic acid hydroxyamide, a novel HDAC inhibitor, in mouse plasma for pharmacokinetic studies.
abstract: A liquid chromatography/tandem mass spectrometric method for the quantification of 6-(3-benzoyl-ureido)-hexanoic acid hydroxyamide (EX-2), a novel histone deacetylase (HDAC) inhibitor, in mouse plasma was developed to support in-house pharmacokinetic (PK) studies in the lead optimization stage. In order to determine the PK parameters for EX-2 in comparison to other HDAC inhibitors such as suberoylanilide hydroxamic acid (SAHA), PXD-101 and LBH-589, which are currently in different stages of clinical trials, research-grade bio-analytical method validations were carried out for EX-2 and these reference HDAC inhibitors, which were synthesized by in-house medicinal chemists. The components of validation consisted of specificity, extraction efficiency, signal-response of calibration standards, lower limit of quantification, autosampler stability and accuracy and precision of quality control samples. The validated LC/MS/MS methods were accurate and precise. The calibration curve ranged from 1 to 1600 ng/mL for all the analytes. The methods developed were used to quantify EX-2 and other HDAC inhibitors in mouse plasma obtained from pharmacokinetic studies. The results suggest that EX-2 has better PK parameters compared with the reference drugs and is a promising drug development candidate.
authors.affiliation: Department of Pharmacokinetics and Drug Metabolism, S*BIO Pte Ltd, 1 Science Park Road, 05-09 The Capricorn, Singapore Science Park II, Singapore 117528.
authors.forename: Pauline
authors.initials: P
authors.lastname: Yeo
authors.forename: Liu
authors.initials: L
authors.lastname: Xin
authors.forename: Evelyn
authors.initials: E
authors.lastname: Goh
authors.forename: Lee Sun
authors.initials: LS
authors.lastname: New
authors.forename: Peizi
authors.initials: P
authors.lastname: Zeng
authors.forename: Xiaofeng
authors.initials: X
authors.lastname: Wu
authors.forename: P
authors.initials: P
authors.lastname: Venkatesh
authors.forename: Ethirajulu
authors.initials: E
authors.lastname: Kantharaj
mesh_terms: D000818:Animals; D002851:Chromatography, High Pressure Liquid / Q000379:methods*; D005260:Female; D056572:Histone Deacetylase Inhibitors; D006877:Hydroxamic Acids / Q000097:blood* / Q000493:pharmacokinetics*; D051379:Mice; D008807:Mice, Inbred BALB C; D015203:Reproducibility of Results; D053719:Tandem Mass Spectrometry / Q000379:methods*
chemical_list: C518248:6-(3-benzoyl-ureido)hexanoic acid hydroxyamide; D056572:Histone Deacetylase Inhibitors; D006877:Hydroxamic Acids