Cyclization of gabapentinoids as a novel approach for their determination by GC-MS/MS in biological fluids

Gabapentinoids are a group of centrally acting depressant drugs and structural analogues of gamma-aminobutyric acid used to treat neurological disorders. Given their narrow therapeutic window, determining their concentrations in physiological fluids, particularly in human blood plasma, is particularly important for monitoring therapeutic efficacy and ensuring patient safety in routine practice. The results obtained in this study using pregabalin, gabapentin, and baclofen demonstrate that preliminary cyclization is significantly more effective for preparing these gabapentinoids for GC analysis than silylation or methylation. The EDAC/DMTMM mixture was identified as the most suitable catalyst for the cyclization of gabapentinoids. The developed procedure results in complete conversion (near 100%) of the investigated gabapentinoids into their cyclic forms. Importantly, matrix components (i.e. plasma/urine components) do not interfere with the catalyzed cyclization process, and no matrix effect is observed. The proposed method is robust and reproducible (about 98%), and the obtained limits of detection and quantification (lower than 0.9 ng/mL and 3.0 ng/mL, respectively) are comparable to those reported in the literature for standard LC-MS methods and significantly lower than those reported for GC-MS methods involving classical derivatization (silylation or methylation) of these analytes. The applicability of the proposed GC signal-enhancement procedure based on preliminary cyclization was confirmed by the analysis of blood and urine samples containing pregabalin, gabapentin, and baclofen. To the best of our knowledge, this is the first report describing the cyclization of gabapentinoids for their determination in biological fluids by GC; thus, the method represents a novel analytical approach.