Simultaneous Determination of Brotizolam and Its Main Hydroxymetabolite in Plasma by Capillary Gas Chromatography with Double Internal Standardization

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Abstract
A gas-liquid chromatographic (GLC) method for the simultaneous determination of brotizolam (I) and its major hydroxymetabolite (1-hydroxymethylbrotizolam) (II) in human plasma is described here. After extraction at pH 13, acid washing, alkaline back extraction and derivatization with a double internal standardization, the analysis was performed on a WSCOT CPsil 5 capillary column, with detection by electron capture. Sensitivity limit was 0.2 ng/ml; reproducibility was about 6–8% for plasma concentrations below 1 ng/ml. No interference of other possible minor hydroxymetabolites of brotizolam was found. Mass fragmentography was used for the validation of hydroxymetabolite derivazation. This method was applied to plasma specimens collected from dogs, after single IV administration of I and II and from healthy volunteers, after single oral administration of 0.5 mg brotizolam. Preliminary pharmacokinetic results are presented here.

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