## 3 Microextraction by Packed Sorbent
[PERSON] and her research group developed several analytical methodologies by employing MEPS as the sample pretreatment technique for the determination of drug substances and related metabolites in both conventional [28; 29; 30; 31; 34; 35; 45] and non-common biological samples [33]. A recent application published in 2024 involved the development of two separate protocols for the extraction of five antidepressant drugs and one metabolite (namely fluoxetine, venlafaxine, \(o\)-desmethylenlafaxine, citalopram, serntraline, and paroxetine) from oral fluid and plasma samples by a mixed-mode C\({}_{8}\)/strong cation exchanger sorbent cartridge and their quantification by GC-MS/MS [28]. The main parameters affecting the extraction procedure, such as the number of draw-eject sample cycles, washing, and elution solvents, were cautiously studied and optimized. Although the whole sample preparation procedure was described as time-consuming and labor-intensive, adequate LLOQ values for all analytes were obtained, and the method could successfully be applied for the quantification of the antidepressants in the context of therapeutic monitoring purposes. In a similar manner, the same research group integrated the MEPS procedure with gas chromatography-tandem mass spectrometry for the determination of several opiates in the urine [29] and whole blood [30] samples of opiate users. In both studies, a C\({}_{8}\)/SCX MEPS sorbent in combination with the use of acid solvents facilitated the sufficient retention of the analytes in the sorbent bed. Taking into consideration their pKa values, the acidic conditions enhanced the positive charge of the determined compounds, while the alkaline elution solvent enabled their desorption from the sorbent. In the first study [30], the authors highlighted low recoveries as the primary disadvantage of the method. This was attributed to the high amounts of present interfering compounds in the blood samples and the low amount of the MEPS sorbent available from the manufacturer, which may impede the interaction of the analytes with the sorbent. Despite this, satisfactory precision and accuracy were observed by using only 250 \(\upmu\)L of sample. In the second study [29], the LOQ was 1 ng/mL for all analytes, except one, and LODs were in the range of 1-10 ng/mL, compared to similar published methods, making the developed method suitable for forensic routine analysis. Two another interesting studies from [PERSON]'s research group involved the development and validation of analytical methods for the identification and quantification of ketamine and its main metabolite worketamine in urine and plasma samples [32] and in hair [33] using MEPS and GC-MS/MS analysis. The first study outlined a simple and rapid protocol that requires only a small sample volume (250 \(\upmu\)L) and eliminates the need for a derivatization step before analysis. This method achieves low detection limits (5 ng/mL) and high recovery rates, ranging from 73% to 101% in urine and 63% to 89% in plasma, for both compounds in biological specimens. In contrast to the first study, in the second, hair samples were used for the determination of the analytes [33]. Hair is considered a non-conventional biological sample, which requires a previous wash and decontamination step before the extraction procedure. Although this step may lead to a laborious and time-consuming sample preparation process, the hair matrix provides a historical record of exposure to drugs and other substances, and thus it can be used for long-term drug detection [47]. Moreover, it is less prone to external conditions (high temperature, rain, drought, etc. ), is not subject to rapid metabolism or excretion, unlike urine and plasma, and allows analyte detection within a wider time window (from weeks to years, depending on the hair length). These facts render hair samples extremely valuable when it comes to forensic investigations and drug testing, such as the ketamine case studies.