TY - JOUR
T1 - A simple, sensitive and reliable LC-MS/MS method for the determination of 7-bromo-5-chloroquinolin-8-ol (CLBQ14), a potent and selective inhibitor of methionine aminopeptidases
T2 - Application to pharmacokinetic studies
AU - Ekpenyong, Oscar
AU - Cooper, Candace
AU - Ma, Jing
AU - Liang, Dong
AU - Olaleye, Omonike
AU - Xie, Huan
N1 - Funding Information:
This work was supported in part by the National Institute of Health SC3 (grant number 1SC3GM102018) and by the National Institute of Health's Research Centers in Minority Institutes Program (grant number 2G12MD007605-22A1).
Funding Information:
This work was supported in part by the National Institute of Health SC3 (grant number 1SC3GM102018 ) and by the National Institute of Health's Research Centers in Minority Institutes Program (grant number 2G12MD007605-22A1 ).
Publisher Copyright:
© 2018 Elsevier B.V.
PY - 2018/10/15
Y1 - 2018/10/15
N2 - CLBQ14 is an 8-hydroxyquinoline analogue that inhibits methionine aminopeptidase (MetAP), an enzyme responsible for the post-translational modification of several proteins and polypeptides. MetAP has been validated as druggable target for some infectious diseases, and its inhibitors have been investigated as potential therapeutic agents. In this study, we developed and validated a liquid chromatography tandem-mass spectrometry (LC-MS/MS) method for the quantification of CLBQ14 in solution, and in rat plasma and urine. This method was applied to the pharmacokinetic evaluation of CLBQ14 in adult male Sprague Dawley (SD) rats. Chromatographic separation was achieved using an ultra-high-performance liquid chromatography (UHPLC) system equipped with Waters XTerra MS C18 column (3.5 μm, 125 Å, 2.1 × 50 mm) using 0.1% formic acid in acetonitrile/water gradient system as mobile phase. Chromatographic analysis was performed with a 4000 QTRAP® mass spectrometer using MRM in positive mode for CLBQ14 transition [M + H]+ m/z 257.919 → m/z 151.005, and IS (clioquinol) transition [M + H]+ m/z 305.783 → m/z 178.917. CLBQ14 was extracted from plasma and urine samples by protein precipitation. The retention times for CLBQ14 and IS were 1.31 and 1.40 min respectively. The standard curves were linear for CLBQ14 concentration ranging from 1 to 1000 ng/mL. The intra-day and inter-day accuracy and precision were found to be within 15% of the nominal concentration. Extraction recoveries were >96.3% and 96.6% from rat plasma and urine respectively, and there was no significant matrix effect from the biological matrices. CLBQ14 is stable in samples subjected to expected storage, preparation, and handling conditions. Pharmacokinetic studies revealed that CLBQ14 has a bi-exponential disposition in SD rats, is extensively distributed with a long plasma half-life and is eliminated primarily by liver metabolism.
AB - CLBQ14 is an 8-hydroxyquinoline analogue that inhibits methionine aminopeptidase (MetAP), an enzyme responsible for the post-translational modification of several proteins and polypeptides. MetAP has been validated as druggable target for some infectious diseases, and its inhibitors have been investigated as potential therapeutic agents. In this study, we developed and validated a liquid chromatography tandem-mass spectrometry (LC-MS/MS) method for the quantification of CLBQ14 in solution, and in rat plasma and urine. This method was applied to the pharmacokinetic evaluation of CLBQ14 in adult male Sprague Dawley (SD) rats. Chromatographic separation was achieved using an ultra-high-performance liquid chromatography (UHPLC) system equipped with Waters XTerra MS C18 column (3.5 μm, 125 Å, 2.1 × 50 mm) using 0.1% formic acid in acetonitrile/water gradient system as mobile phase. Chromatographic analysis was performed with a 4000 QTRAP® mass spectrometer using MRM in positive mode for CLBQ14 transition [M + H]+ m/z 257.919 → m/z 151.005, and IS (clioquinol) transition [M + H]+ m/z 305.783 → m/z 178.917. CLBQ14 was extracted from plasma and urine samples by protein precipitation. The retention times for CLBQ14 and IS were 1.31 and 1.40 min respectively. The standard curves were linear for CLBQ14 concentration ranging from 1 to 1000 ng/mL. The intra-day and inter-day accuracy and precision were found to be within 15% of the nominal concentration. Extraction recoveries were >96.3% and 96.6% from rat plasma and urine respectively, and there was no significant matrix effect from the biological matrices. CLBQ14 is stable in samples subjected to expected storage, preparation, and handling conditions. Pharmacokinetic studies revealed that CLBQ14 has a bi-exponential disposition in SD rats, is extensively distributed with a long plasma half-life and is eliminated primarily by liver metabolism.
KW - 8-Hydroxyquinoline
KW - Bio-analytical method development
KW - LC-MS/MS
KW - Pharmacokinetics
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U2 - 10.1016/j.jchromb.2018.08.027
DO - 10.1016/j.jchromb.2018.08.027
M3 - Article
C2 - 30199748
AN - SCOPUS:85052931109
VL - 1097-1098
SP - 35
EP - 43
JO - Journal of Chromatography B: Analytical Technologies in the Biomedical and Life Sciences
JF - Journal of Chromatography B: Analytical Technologies in the Biomedical and Life Sciences
SN - 1570-0232
ER -