Abstract
Methods to monitor the metabolic transformations of pharmaceuticals in a real-time and rapid fashion are required to develop safe and effective drugs. Lactone hydrolysis is one of the most important metabolic transformations; it occurs readily in pharmaceuticals containing lactones by both enzymatic and non-enzymatic processes. In this study, a novel strategy that combines three-way excitation–emission-kinetic (EEM-kinetic) fluorescence data with second-order calibration method based on alternating normalization-weighted error (ANWE) algorithm was developed to monitor the lactone hydrolysis of irinotecan (CPT-11). Accurate real-time concentrations together with reasonable resolutions of the excitation and emission profiles could be estimated for both the lactone form (CPT-11-L) and carboxylate form (CPT-11-C) of CPT-11 during its hydrolysis, even when the fluorescence spectra of CPT-11-L and CPT-11-C seriously overlapped with each other and unknown fluorescent components coexisted in the plasma. Satisfactory results were obtained for static validation samples, spiked plasma samples, and kinetic samples. The average recoveries of CPT-11-L and CPT-11-C in three types of samples mentioned above ranged from 83.7% to 116.7%. The lactone hydrolysis of CPT-11 follows 1st-order degradation kinetics with rate constants of 0.0318±0.0031min−1 and 0.0323±0.0008min−1, and half-lives of 21.9±2.0min and 21.5±0.5min in PBS and plasma samples, respectively. The strategy described herein minimized or eliminated traditionally time-consuming sample pre-treatments and facilitated the quantification of the target drug in its native environment. This method was proved to be simple, real-time, fast, low-cost, high-efficiency and can be potentially applied to other types of dynamic systems.
Published Version
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