Analytical Approaches for the Determination of Lidocaine and Its Metabolites: A Comprehensive Insight

Lidocaine (LID), an amide-type local anesthetic and antiarrhythmic agent, remains one of the most extensively used drugs in medical, dental, and surgical practice owing to its rapid onset, potent analgesic activity, and reversible nerve-blocking effects. However, its narrow therapeutic index, rapid hepatic metabolism, and typically low plasma concentrations necessitate the development of highly sensitive and selective analytical approaches for accurate quantification in biological, pharmaceutical, and environmental matrices. This review provides a comprehensive and critical evaluation of more than two decades of methodological progress in LID and metabolites analysis (monoethylglycinexylidide (MEGX) and glycinexylidide (GX)). High-performance liquid chromatography (HPLC) and liquid chromatography-tandem mass spectrometry (LC-MS/MS) have emerged as the gold-standard techniques due to their superior sensitivity, reproducibility, and specificity at trace levels. Complementary spectrophotometric, electroanalytical, and capillary electrophoresis methods also demonstrate distinct advantages in cost, simplicity, and eco-sustainability. Recent advancements highlight the integration of Artificial Intelligence (AI) and Machine Intelligence (MI) algorithms to enhance data processing, optimize chromatographic conditions, and improve pattern recognition in complex matrices, thereby enabling automated, real-time analysis with higher precision. Persistent analytical challenges such as matrix interference, compound instability, and ultra-trace detection underscore the need for continued innovation. Future perspectives emphasize the combination of AI-driven modeling, nanomaterial-based sensors, and green analytical platforms to establish smart, miniaturized, and environmentally sustainable systems for LID determination, facilitating reliable pharmacokinetic monitoring, clinical diagnostics, and pharmaceutical quality assurance.