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KMID : 0370220190630020075
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Yakhak Hoeji
2019 Volume.63 No. 2 p.75 ~ p.81
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Quantification of a Novel Aldehyde Dehydrogenase Inhibitor in Rat Using Liquid Chromatography-quadrupole Time-of-flight Mass Spectrometric Method and Its Application to Pharmacokinetic Modeling in Rat
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Kim Na-Hye
Park Yu-Ri
Lee Byeong-Ill
Park Min-Ho
Shin Seok-Ho
Byeon Jin-Ju
Choi Jang-Mi
Shin Young-G.
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Abstract
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Aldehyde dehydrogenase 1A1 (ALDH1A1) is an enzyme acting subsequent to alcohol dehydrogenase in the major pathway of alcohol metabolism. In addition, ALDH1A1 has been known to be involved in the oxidation of retinaldehyde to retinoic acid (RA), acting as transcriptional regulators. It is well known that ALDH1A1 is overexpressed in cancer stem cells and plays an important role in the biology of cancer. During screening compounds for ALDH1A1 inhibition, a novel molecule, Compound A (2-[1-(3-ethoxycarbonyl-4,5,6,7-tetrahydro-1-benzothiophen-2-yl)-2,5-dioxopyrrolidin-3-yl] sulfanyl benzoic acid) was found in the NIH chemical libraries. In this study, a liquid chromatographic-quadrupole timeof- flight mass spectrometric (LC-TOF-MS) method was developed for the quantification of Compound A in pharmacokinetic (PK) study in rat. Two M HCl was added before protein precipitation to stabilize Compound A in rat plasma. A quadratic regression (weighted 1/concentration) was used to fit calibration curves over the concentration range of 81.48-19800 ng/mL for Compound A. Using the time-concentration PK profile in rat, two-compartment model was selected as the PK prediction model. In addition, parameter sensitivity analysis was used to evaluate the PK parameters affecting the exposure of Compound A.
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KEYWORD
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aldehyde inhibitor, LC-TOF-MS, quantification, pharmacokinetic modeling
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