An integrated microsampling approach based on solid-phase microextraction (SPME) was developed to provide a complete solution to highly efficient and accurate pharmacokinetic studies. The microsampling system included SPME probes that are made of poly(ethylene glycol) (PEG) and C18-bonded silica, a fast and efficient sampling strategy with accurate kinetic calibration, and a high-throughput desorption device based on a modified 96-well plate. The sampling system greatly improved the quantitative capability of SPME in two ways. First, the use of the C18-bonded silica/PEG fibers minimized the competition effect from analogues of the target analytes in a complicated sample matrix such as blood or plasma samples, which is a common problem associated with solid coating SPME fibers for quantitative analysis. Moreover, the C18-bonded silica/PEG fibers provide high sensitivity and a large dynamic range that covers the possible sample concentration range during diazepam administration and elimination. Second, the kinetic calibration method offers more accurate quantitation than the calibration curve method for in vivo SPME, because it compensates for convection and matrix effects during sampling. Therefore, it is especially suitable as a fast sampling technique for pre-equilibrium SPME. Furthermore, with the high-throughput desorption device, the integrated system offers compactness and high efficiency. Its feasibility for in vivo sampling was demonstrated by monitoring diazepam pharmacokinetics and validated by conventional chemical assays and equilibrium SPME. In addition, we propose a simple method to determine the apparent distribution constant between an SPME fiber and a blood matix (Kfs) and the distribution constant between an SPME fiber and a pure PBS buffer sample matrix (Kfb). As a result, both total and free concentrations of the drug and its metabolites can be detected simultaneously. Accordingly, the binding constants to the blood matrix can be obtained, which are of special significance for clinical diagnosis and drug discovery.

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The on-fiber standardization technique for solid-coated solid-phase microextraction (SPME) was studied, and a theoretical model is proposed for the isotropic behavior of adsorption and desorption, based on Fick's law of diffusion and the Langmuir model. The isotropy of the adsorption and desorption of analytes onto and from the surface of porous solid SPME fiber was validated with the use of a commercially available fiber, a 50-µm Carbowax/ templated resin for carbamate pesticide analysis in various sample matrixes, and a self-made polypyrrole fiber for diazepam analysis in blood samples. Time constants were comparable for the adsorption and desorption processes. Equilibrium constants and fiber capacities were calculated with the Langmuir isotherm model. A kinetic method was developed to calibrate adsorption using desorption. This calibration corrected for the sample matrix effects and minimized displacement effects as a pre-equilibrium extraction. The technique was successfully applied to the analysis of pesticides in river water and white wine as well as drug analysis in clinical plasma and whole blood samples. Solid-phase microextraction (SPME) was first documented byPawliszyn's group in 1990. 1 The valuable sampling technology is fast, simple, and solvent-free and combines sampling, sample preparation, and preconcentration to the extraction phase into one single step. 2 It has been widely applied in environmental monitoring, industrial hygiene, process monitoring, and clinic, forensic, food, flavor, fragrance, and drug analyses, in laboratory, and onsite analyses. 3 There are two types of SPME coatings, including liquid and solid phases. Poly(dimethylsiloxane) (PDMS) and polyacrylate (PA) are liquid coatings. PDMS is the most widely used coating for the analysis of volatile organic compounds (VOCs) such as benzene, toluene, ethylbenzene, and xylene (BTEX), polycyclic aromatic hydrocarbons, odor, and flavor. Both PDMS and PA

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Solid-phase microextraction probes based on poly(ethylene glycol)/C18-bonded silica were used for in vivo monitoring of drugs from circulating blood of beagles, over a period of 8 h. After sampling, the extracted drugs were subsequently quantified by liquid chromatography coupled with tandem mass spectrometry. External calibrations in whole blood and phosphate-buffered saline were used to correlate the amount of analytes extracted in regard to the total and free concentrations in blood respectively. The probe provided sufficient sensitivity for the drugs in the blood matrix, while the need for drawing blood was eliminated. The limit of detections of the method from whole blood were 1.7, 1.4 and 2.8 ng mL(-1) for the analysis of diazepam, nordiazepam and oxazepam respectively, and the linear range was from 4 ng mL(-1) to 2 microg mL(-1). The method was applied for the monitoring of pharmacokinetic profiles of intravenous administration of diazepam and its two main metabolites in dogs, and the results were compared with profiles determined by conventional methods. This approach offered increased sensitivity and accuracy, short extraction time, and convenient calibration for in vivo sampling for dynamic monitoring.

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