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Keywords

Enantiaomers, Chiral Seperation, Plasma, HPLC

Abstract

ML-1035, is a gastroprokinetic agent structrually related to metoclopramide. Because ML-1035 contains an asymmetric chiral sulfoxide moiety, a chiral HPLC method was developed to separate and quantitate its R and S enantiomers in plasma. The ML-1035 enantiomers present in plasma were extracted with dichloroethane under alkaline conditions. The extract was evaporated to dryness and reconstituted in the mobile phase. The samples were chromatographed on a Chiralcel OD HPLC column with hexane: absolute ethanol (1% TEA) with a ratio of 1:1 (v/v) as the mobile phase. The enantiomers of the unchanged drug were quantified by fluorescence detection (ex: 310 nm, em: 350 nm). The method provided a linear response for both enantiomers over a concentration range of 25 (limit of quantitation)to 2500 ng/ml with correlation coefficients of 0.9987 or greater. The interassay precision was 9.5% or less and the accuracy ranged from 93.9% to 103.4% of the theoretical value. This method was utilized in determining the plasma concentrations of the R and S enantiomers following oral and intravenous administration of R or S enantiomers to dogs. The method was also adapted to measure enantiomer levels from in vitro reaction mixtures so that the possibility of metabolic inversion could be assessed. The data suggest that no significant level of inversion between the enantiomers occurred either in vivo or in vitro.

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