STEREOSELECTIVE DETERMINATION OF R(-)-MK-571 AND S(+)-MK-571, A LEUKOTRIENE-D4 ANTAGONIST, IN HUMAN PLASMA BY CHIRAL HIGH-PERFORMANCE LIQUID-CHROMATOGRAPHY

被引:8
作者
ROBINETT, RSR [1 ]
HSIEH, JYK [1 ]
机构
[1] MERCK SHARP & DOHME LTD,W POINT,PA 19486
来源
JOURNAL OF CHROMATOGRAPHY-BIOMEDICAL APPLICATIONS | 1991年 / 570卷 / 01期
关键词
D O I
10.1016/0378-4347(91)80210-4
中图分类号
O65 [分析化学];
学科分类号
070302 ; 081704 ;
摘要
A stereoselective high-performance liquid chromatographic method that utilizes fluorescence detection was developed for the selective and sensitive quantification of R(-)- and S(+)-enantiomers of MK-571 (1), a potent and specific leukotriene D4 antagonist, in human plasma. Racemic 1 was isolated from the acidified plasma using solid-phase extraction and the resulting residue was successfully reacted with isobutyl chloroformate and R(+)-1-(1-naphthyl)ethylamine in triethylamine-acetonitrile medium to form the diastereomer of each enantiomer. A structural analogue of 1 was used as internal standard. The derivatized sample was dissolved in 1,1,2-trichlorotrifluoroethane and an aliquot was chromatographed on a (R)-urea chiral column using a mobile phase containing 89% triethylamine-pentane (3:1000, v/v), 10% 2-propanol, and 1% acetonitrile at a flow-rate of 1.5 ml/min. The fluorescence response (excitation wavelength, 350 nm; emission wavelength, 410 nm) was linear (r2 > 0.999) for concentrations of enantiomers of 1 from 0.05-mu-g/ml, the lowest quantitation limit, up to 2.5-mu-g/ml. Intra-day coefficients of variation at 0.05-mu-g/ml were 2.4% for the R(-)-isomer and 2.0% for S(+)-isomer. The corresponding inter-day coefficients of variation for R(-)- and S(+)-1 were 2.6 and 3.6%, respectively. The utilit of the methodology was established by analysis of plasma samples from male volunteers receiving single intravenous and oral doses of racemic 1.
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页码:157 / 165
页数:9
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