ABSTRACT
Antimicrobial agents (AMAs) are widely exploited nowadays to meet the high demand for animal-derived food. It has a significant impact on the food chain whose end consumers are human beings. The burden of AMAs on humans comes from either meat or crops cultivated on soil containing high residual antibiotics, which are responsible for the global crisis of antibiotic resistance. Thus, the objective of this study was to design a selective and sensitive liquid chromatography-mass spectrometry (LC-MS)/MS-based simultaneous bioanalytical method for estimation of twenty AMAs in human plasma, raw meat, and soil samples. The selective extraction of all analytes from the above matrices was performed by the solid-phase extraction clean-up method to overcome the interferences. Analytes were separated on a Waters Symmetry Shield C18 (150 × 4.6 mm2, 5 µm) column, using an isocratic solvent system of methanol-0.5% formic acid (80:20, v/v) with 0.75 mL/min flow rate. The average extraction recoveries for all analytes in plasma were ranged from 42.0 to 94.0% with relative standard deviations (RSDs) below ±15%. All of the validation parameters are in accordance with the United State Food and Drug Administration (USFDA) guidelines. Moreover, the method was also valid for a broad plasma concentration range and can be proposed as an excellent method for routine pharmacokinetic studies, therapeutic drug monitoring, clinical analysis, and detection and quantitation of AMA remnants in raw meat as a standard quality control test for human consumption.
ABSTRACT
The objective of this work was to evaluate the feasibility of transdermal delivery of two widely prescribed dementia drugs for the Alzheimer's disease. In this regard, the drug in adhesive patches of memantine (ME) co-loaded with donepezil (DO) was prepared using an ethylene vinyl acetate polymer and characterized for drug content, the crystallinity of drugs in the polymer matrix, and in vitro permeation. To understand the different physical and chemical processes underlying the percutaneous absorption, it is required to employ a comprehensive model that accounts for the anatomy and physiology of the skin. A transdermal physiologically based pharmacokinetic (TPBPK) model was developed and was integrated in a compartmental pharmacokinetic model to predict the plasma drug concentrations in rats. The model predictions showed a good fit with the experimental data, as evaluated by the prediction error calculated for both drugs. It was evident from the simulations that the drug diffusivity and partition coefficient in the polymer matrix are the critical parameters that affect the drug release from the vehicle and subsequently influence the in vivo pharmacokinetic profile. Moreover, a correlation function was built between the in vitro permeation data and in vivo absorption for both ME and DO. A good point-to-point in vitro/in vivo correlation (IVIVC, Level A correlation) was achieved by predicting the plasma concentrations with convolution for the entire study duration. The results of our study suggested that the implementation of mechanistic modeling along with IVIVC can be a valuable tool to evaluate the relative effects of formulation variables on the bioavailability from transdermal delivery systems.
