Pauline Yeo1, Xin Liu1, Evelyn Mei Ling Goh1, Lee Sun New1, Peizi Zeng1, Xiaofeng Wu1, Venkatesh Paramesh1, Kantharaj Ethirajulu1
1Department of Pharmacokinetics and Drug Metabolism, S*BIO Pte Ltd, 1 Science Park Road, 05‐09 The Capricorn, Singapore Science Park II, Singapore 117528.
Tóm tắt
AbstractA 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. Copyright © 2007 John Wiley & Sons, Ltd.
