Published: Journal of Analytical Toxicology, Volume 22, Number 5, September 1998, pp. 374–382.

Isotope Dilution Gas Chromatographic–Mass Spectrometric Measurement of Tricyclic Antidepressant Drugs. Utility of the 4-Carbethoxyhexafluorobutyryl Derivatives of Secondary Amines
Barbara A. Way, Douglas Stickle, Mary E. Mitchell, John W. Koenig, and John Turk

Stable isotope dilution gas chromatographic–mass spectrometric (GC–MS) measurement of tricyclic antidepressants (TCA) is a useful alternative to high-performance liquid chromatography (HPLC) methods when interfering substances prevent accurate quantitation by HPLC. For satisfactory GC–MS analysis, secondary amine TCA must be derivatized. Commonly employed trifluoroacetyl and heptafluorobutyryl derivatives are relatively unstable and cause rapid deterioration of capillary GC columns. Therefore we examined 4-carbethoxyhexafluorobutyryl chloride (CHFB-Cl) as an alternative derivatizing agent and developed a stable isotope dilution GC–MS method employing ring-labeled [²H₄]-desipramine and [²H₄]-imipramine internal standards, which permits measurement of desipramine, nortriptyline, imipramine, and amitriptyline in plasma samples containing one or all of these analytes. The GC–MS assay is linear for each analyte from the lower limit of quantitation (25 ng/mL) up to 1500 ng/mL and correlates well with HPLC measurements. The GC–MS analytic coefficient of variation was 9.7 ± 1.3% for all analytes considered together. Although interferences are observed in the HPLC assay, thioridazine, perphenazine, cyclobenzaprine, and norcyclobenzaprine do not interfere with GC–MS measurements of the TCA examined here. The stability of the CHFB derivative of secondary amine TCA was found to be superior to that of the trifluoroacetyl derivatives of these compounds.

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