Journal of Chromatography B 2011-06-01

Determination of midazolam and 1-hydroxymidazolam from plasma by gas chromatography coupled to methane negative chemical ionization mass spectrometry after sublingual administration of midazolam.

Ruut Kaartama, Pekka Jarho, Jouko Savolainen, Hannu Kokki, Marko Lehtonen

文献索引：J. Chromatogr. B. Analyt. Technol. Biomed. Life Sci. 879(19) , 1668-76, (2011)

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摘要

A sensitive and selective gas chromatographic mass spectrometric method for the determination of midazolam and its biologically active metabolite, 1-hydroxymidazolam, in rabbit plasma has been developed and validated. Sample preparation includes mixed-mode solid-phase extraction and derivatization with silylating reagents. Midazolam-d4 was used as an internal standard for the determination of parent drug and its active metabolite. The instrumentation consisted of a capillary column gas chromatography and a single quadrupole mass spectrometer with a negative chemical ionization. The method was found to be valid in terms of selectivity, linearity, precision, accuracy, and recovery over the concentration range of 2-200 ng/ml and 1-100 ng/ml for midazolam and 1-hydroxymidazolam, respectively. For both analytes, the lower limit of quantification was 2 ng/ml. Midazolam was stable in stock solutions stored three months at -20°C and in human plasma stored for three months at -80°C. In addition, no degradation of midazolam was found after three freeze-thaw cycles, in short-term stability at room temperature for 24h, or in post-preparative stability in the autosampler. The validity of the method was further tested by performing a pharmacokinetic study of sublingual administration of midazolam in rabbits. The method will be used in studies related to a formulation development of novel midazolam formulations for use in paediatric anaesthesia.Copyright © 2011 Elsevier B.V. All rights reserved.