Isotope Dilution Gas Chromatographic-Mass Spectrometric Measurement of Tricyclic Antidepressant Drugs. Utility of the 4-Carbethoxyhexafluorobutyryl Derivatives of Secondary Amines

• Published in: Journal of analytical toxicology Vol. 22; no. 5; pp. 374 - 382
• Main Authors: Way, Barbara A., Stickle, Douglas, Mitchell, Mary E., Koenig, John W., Turk, John
• Format: Journal Article
• Language: English
• Published: Niles, IL Oxford University Press 01-09-1998; Preston
• Subjects: Amitriptyline - blood; Analysis; Antidepressive Agents, Tricyclic - blood; Biological and medical sciences; Chromatography, High Pressure Liquid; Desipramine - blood; Deuterium; Drug Stability; Fluorocarbons - chemistry; Gas Chromatography-Mass Spectrometry - methods; General pharmacology; Humans; Indicators and Reagents - chemistry; Medical sciences; Nortriptyline - blood; Pharmacology. Drug treatments; Reference Standards; Reproducibility of Results; Electron impact; Biological fluid; Nortriptyline; Amitriptyline; Chemical analysis; Desipramine; Nitrogen heterocycle; Coupled method; Psychotropic; HPLC chromatography; Isotope dilution; Tricyclic compound; Derivatization; Blood plasma; Gas chromatography; Imipramine; Antidepressant agent; Qualitative analysis; Aromatic compound; Mass spectrometry; Secondary amine; Comparative study; Acylation; Quantitative analysis
• ISSN: 0146-4760; 1945-2403
• DOI: 10.1093/jat/22.5.374

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-CI) 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.