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采用柱前衍生化反相高效液相色谱法分析氟比洛芬、酮洛芬和依托度酸对映体及其在人血浆中与蛋白质结合的应用。

Analysis of flurbiprofen, ketoprofen and etodolac enantiomers by pre-column derivatization RP-HPLC and application to drug-protein binding in human plasma.

作者信息

Jin Yin-Xiu, Tang Yi-Hong, Zeng Su

机构信息

Department of Pharmaceutical Analysis and Drug Metabolism, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, Zhejiang 310058, PR China.

出版信息

J Pharm Biomed Anal. 2008 Apr 14;46(5):953-8. doi: 10.1016/j.jpba.2008.01.038. Epub 2008 Feb 3.

Abstract

A stereoselective reversed-phase high-performance liquid chromatography (HPLC) assay to determine the enantiomers of flurbiprofen, ketoprofen and etodolac in human plasma was developed. Chiral drug enantiomers were extracted from human plasma with liquid-liquid extraction. Then flurbiprofen and ketoprofen enantiomers reacted with the acylation reagent thionyl chloride and pre-column chiral derivatization reagent (S)-(-)-alpha-(1-naphthyl)ethylamine (S-NEA), and etodolac enantiomers reacted with S-NEA using 1-(3-dimethylaminopropyl)-3-ethyl-carbodiimide (EDC) and 1-hydroxybenzotriazole (HOBT) as coupling agents. The derivatized products were separated on an Agilent Zorbax C18 (4.6 mm x 250 mm, 5 microm) column with a mixture of acetonitrile-0.01 mol.L(-1) phosphate buffer (pH 4.5) (70:30, v/v) for flurbiprofen enantiomers, acetonitrile-0.01 mol.L(-1) phosphate buffer (pH 4.5) (60:40, v/v) for ketoprofen enantiomers and methonal-0.01 mol.L(-1) potassium dihydrogen phosphate buffer (pH 4.5) (88:12, v/v) for etodolac enantiomers as mobile phase. The flow of mobile phase was set at 0.8 mL.min(-1) and the detection wavelength of UV detector was set at 250 nm for flurbiprofen and ketoprofen enantiomers and 278 nm for etodolac enantiomers. The assay was linear from 0.5 to 50 microg.mL(-1) for each enantiomer. The inter- and intra-day precision (R.S.D.) was less than 10% and the average extraction recovery was more than 87% for each enantiomer. The limit of quantification for the method was 0.5 microg.mL(-1) (R.S.D.<10%, n=5). The method developed was used to study the drug-protein binding of flurbiprofen, ketoprofen and etodolac enantiomers in human plasma. The results showed that the stereoselective binding of etodolac enantiomer was observed and flurbiprofen and ketoprofen enantiomers were not.

摘要

建立了一种用于测定人血浆中氟比洛芬、酮洛芬和依托度酸对映体的立体选择性反相高效液相色谱(HPLC)分析法。采用液-液萃取法从人血浆中提取手性药物对映体。然后,氟比洛芬和酮洛芬对映体与酰化试剂亚硫酰氯和柱前手性衍生化试剂(S)-(-)-α-(1-萘基)乙胺(S-NEA)反应,依托度酸对映体以1-(3-二甲氨基丙基)-3-乙基碳二亚胺(EDC)和1-羟基苯并三唑(HOBT)作为偶联剂与S-NEA反应。衍生化产物在Agilent Zorbax C18(4.6 mm×250 mm,5μm)柱上分离,氟比洛芬对映体的流动相为乙腈-0.01 mol·L⁻¹磷酸盐缓冲液(pH 4.5)(70:30,v/v),酮洛芬对映体的流动相为乙腈-0.01 mol·L⁻¹磷酸盐缓冲液(pH 4.5)(60:40,v/v),依托度酸对映体的流动相为甲醇-0.01 mol·L⁻¹磷酸二氢钾缓冲液(pH 4.5)(88:12,v/v)。流动相流速设定为0.8 mL·min⁻¹,紫外检测器对氟比洛芬和酮洛芬对映体的检测波长设定为250 nm,对依托度酸对映体的检测波长设定为278 nm。该分析法对每种对映体的线性范围为0.5至50μg·mL⁻¹。每种对映体的日间和日内精密度(相对标准偏差)均小于10%,平均萃取回收率均大于87%。该方法的定量限为0.5μg·mL⁻¹(相对标准偏差<10%,n = 5)。所建立的方法用于研究人血浆中氟比洛芬、酮洛芬和依托度酸对映体与蛋白质的结合情况。结果表明,观察到依托度酸对映体存在立体选择性结合,而氟比洛芬和酮洛芬对映体不存在。

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