# Solid Phase-Based Microextraction Techniques in Therapeutic Drug Monitoring
## 3 Sample Pretreatment--Solid Phase-Based Microextraction Techniques
### Solid-Phase Microextraction and in-Tube Solid-Phase Microextraction
& HPLC-UV &  
\begin{table}
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**Analyles** & **Sample (Amount)** & **Sample Pretreatment and Extraction Procedure** & **Analytical Technique** & **LOD; LOQ** & **Linear Range** & **Ref. ** \\ \hline \multirow{8}{*}{Tanneamic acid} & \multirow{8}{*}{n.a. of plasma and urine} & SPME (hydrophilic-lipophilic balance (HLR) coated) & \multirow{8}{*}{LC-MS/MS (n.a.)} & \multirow{8}{*}{LC-MS/MS (n.  
SPME and in-tube SPME have been applied for the extraction of many drugs in different biological samples. [PERSON] et al. [35] developed a methodology for the determination of drugs for the treatment of [PERSON]'s disease in plasma samples using in tube-SPME and hydrophilic interaction chromatography coupled with tandem mass spectrometry. With only 200 \(\upmu\)L of sample, the five drugs showed LOQ values between 1.2 and 170 ng/mL, and the method was applied to authentic samples. Using SPME, [PERSON] et al. [36] established a method for the determination of five antipsychotics in blood and urine. With ultra-performance liquid chromatography coupled to tandem mass spectrometry (UPLC-MS/MS) analysis, the authors were able to determine the analytes at sub-therapeutic values with LOQs between 12.5 and 25 pg/mL, with the only disadvantage of the high volume of urine applied (10 mL). More recently, [PERSON] et al. [39] developed a method for the determination of immunosuppressants such as tacrolimus, sirolimus, everolimus and cyclosporine A in 200 \(\upmu\)L of blood samples, with extraction by matrix-compatible solid-phase microextraction fibers (BioSPME) and analysis by microfluidic open interface coupled with tandem mass spectrometry. Comparing with the work mentioned in the previous section by [PERSON] and [PERSON] [19], and although with values of limits of detection (LOD) and LOQs not equally low, these authors also validated the method with linearity between 1 and 50 ng/mL for tacrolimus, sirolimus and everolimus, and applied the methodology to samples from patients undergoing immunosuppression therapy. [PERSON] et al. [41] developed a method for the biomoritoring of four metabolites of organophosphate flame retardants, for screening them to assess exposure risk for humans and for their potential application in epidemiological studies on individual exposures in large populations. [PERSON] et al. [42] established a method for determining the plasma protein binding of drugs in plasma samples for atenol, morphine, acetaminophen, lorazepam, carbamazepine, diazepam and buprenorphine. Applying BioSPME (C18) as the extraction technique, the authors believe that this measurement is essential during drug development, for pharmacokinetic and pharmacodynamic studies and in clinical practice since it is important for TDM and personalized medicine. Although without validation data, [PERSON] et al. [43] developed a methodology for the detection of doxorubicin in vivo lung perfusion with extraction by BioSPME (C8+benzenesulfonic acid particles) for targeting residual micrometastatic disease, demonstrating the potential of the technique for real-time monitoring of the administered chemotherapy and the usefulness in adapting the strategy to personalized treatment. Pipette Tip Solid-Phase Extraction, Micro Solid-Phase Extraction and Dispersive Solid-Phase Extraction or Matrix Solid-Phase Dispersion  
Pipette tip SPE is routinely used in several areas. All sample manipulations are performed by aspiration and disposal through a pipette tip using a micropipette. Of the commercially available materials, the most used are mixed-mode cation exchange and C18 solvents. This technique is simpler, fast, uses disposable materials and, given the small volume of the bed and the mass of the sorbent inside the tip, aims to minimize the volumes of specimen and organic solvents required for the conditioning and elution steps, accelerating the evaporation step process and providing higher yield and lower costs [28; 44; 45].