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Optimization of a rapid method for screening drugs in blood by liquid chromatography tandem mass spectrometry

  • Alba M. Rodrigo Valero EMAIL logo , Oscar Quintela Jorge , Begoña Bravo Serrano and Sara Ayuso Tejedor
Published/Copyright: November 23, 2023
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Advances in Laboratory Medicine / Avances en Medicina de Laboratorio
From the journal Advances in Laboratory Medicine / Avances en Medicina de Laboratorio Volume 4 Issue 4

Abstract

Objectives

In the recent years, liquid chromatography with tandem mass spectrometry has gained popularity in laboratories. This technique has a higher specificity, detects different analytes from a single specimen, measures analytes in distinct matrices, and substantially reduce analytical interference, with respect to immunoassay. The processing and preparation of biological samples are crucial in chromatography. Interferences in blood testing are usually caused by the presence of phospholipids and proteins. The main objective of this study was to improve analytical processes for drug screening by LC-MS/MS using a novel blood sample preparation method based on protein precipitation and removal of phospholipids.

Methods

An evaluation was performed of a new method for the preparation of blood samples based on protein precipitation and removal of phospholipids by LC-Q-q-LIT.

Results

Limit of detection, limit of quantification and measurement range were determined for 56 molecules. The results of 11 cases were compared with those obtained using standard blood collection methods and instruments.

Conclusions

The novel blood preparation and testing method based on LC-Q-q-LIT, a more sensitive technique, has demonstrated to yield comparable results to traditional methods. In addition, this new technique reduces turnaround time and costs.

Keywords: screening; removal of phospholipids; mass spectrometry; protein precipitation; blood

Introduction

In the last 10–15 years, liquid chromatography-tandem mass spectrometry has gained popularity in clinical laboratories [1, 2]. Benefits of this analytical technique include a higher specificity, the possibility of measuring different analytes in a single sample injection, measuring analytes in different matrices, and a dramatic reduction of analytical interferences, as compared to immunoassay [3]. Notably, immunoassay is still used in many laboratories as the gold-standard method for screening drugs in blood. However, positive results require confirmation by chromatography-tandem mass spectrometry [4].

In the field of clinical and forensic toxicology, the compounds to be detected are unknown a priori. In these cases, immunoassays are insufficient, as they screen for a limited number of potentially present substances (or substance families) and lack the required sensitivity and selectivity. Therefore, more effective laboratory strategies are necessary (Systematic Toxicological Analysis, STA) to be able to identify hundreds of relevant toxic substances in biological samples and ensure a correct interpretation of results [5]. This strategy is structured into two stages. Firstly, screening is performed for some drugs and medicines in urine and blood by immunoassay. Secondly, the results obtained in the first stage are confirmed via extended screening for substances that were not included in the first stage. The main analytical techniques used include: HS-GC-FID, GC-MS, GC-MS/MS, LC-MS/MS, with the latter including high-resolution mass spectrometry (LC-HR-MS).

The processing and preparation of biological samples is crucial in chromatography. Their relevance stems from the need to concentrate or remove the different components of the sample that may interfere with results. This step ensures appropriate chromatographic separation and efficacy. The aim of the preanalytical stage, including sample preparation, is to concentrate target substances while removing potential endogenous interfering substances from the biological matrix. The presence of proteins, lipids, salts and cellular components may interfere with the measurement of the analyte under study and condition chromatography performance. The main sample preparation procedures include filtration, centrifugation, dilution, protein precipitation, liquid–liquid extraction (LLE) and solid-phase extraction (SPE). The two latter are the most common techniques for blood and urine testing in clinical toxicology [6]. Despite the advantages of these procedures, most of them may cause a partial component loss. In addition, not all methods eliminate interfering substances completely. The main interfering substances when screening for drugs in blood are phospholipids and proteins. Therefore, sample preparation should be aimed at reducing their presence as much as possible. For this reason, we suggest integrating a special sample (serum or plasma) preparation procedure combining protein precipitation and removal of phospholipids in the preanalytical stage instead of traditional SPE and LLE extractions [7] as it has some advantages. Firstly, it reduces turnaround time, since it is a less time-consuming method. Secondly, being less selective, this technique favors the detection of a higher number of components, as compared to traditional techniques. Its lower selectivity is due to the fact that analytes with very different chemical structures and/or polarity are not removed, as it does occur during SPE and LLE.

The main objective of this study was to improve STA based on LC-MS/MS by using a novel method. This method integrates a new step in blood sample preparation that involves protein precipitation and removal of phospholipids. Performance for qualitative and quantitative analysis of the selected molecules was assessed in terms of limit of detection, and linearity, precision and accuracy, respectively. Likewise, we evaluated its applicability through the analysis of 11 real-life samples received in the INTCF in Madrid. Results were compared with those obtained with traditional extraction methods and instruments.

Materials and methods

Reagents, stock and working solutions

The following deuterated internal standards were obtained from Cerilliant® (Round Rock, TX, USA): clomipramine-d3, ketamine-d4, oxazepam-d5, pseudoephedrine-d3, risperidone-d4, salbutamol-d3, tramadol-d3 and zolpidem-d6. LC-MS acetonitrile, LC-MS formic acid, 0.1 % (v/v) formic acid solution in water and 0.1 % (v/v) formic acid solution in LC-MS grade acetonitrile were obtained from Fisher Scientific® (Waltham, MA, USA). 1 M ammonium formate was obtained from Honeywell® (Charlotte, NC, USA) and 0.1 M ZnSO4 from Panreac Química S.L.U (Castellar del Vallès, Barcelona, Spain). Deionize water was obtained using a Millipak® filter from Merck-Millipore® (Burlington, MA, USA) formed by a 0.22 µm filtration membrane.

Regarding working solutions, the 0.1 M ZnSO4 solution was used for cell lysis and the LC-MS grade acetonitrile (ACN) solution acidified with formic acid (FA) 1 % (v/v) was used for protein precipitation. In addition, the solution of deuterated internal standards was prepared at the known concentration of 0.1 mg/L for analyte quantification. Finally, the mixture for sample reconstitution was also prepared with 90 % water and 10 % ACN, both acidified with 0.1 % (v/v) FA.

The 56 drugs under study were grouped according to their therapeutic group in the following way to facilitate the experimental work; group 1: clobazam, clotiazepam, flunitrazepam, flurazepam, nitrazepam, prazepam, group 2: midazolam, oxazepam, temazepam, tetrazepam, triazolam, zolpidem, group 3: bentazepam, chlordiazepoxide, diazepam, lorazepam, lormetazepam, nordiazepam, group 4: amitriptyline, citalopram, clomipramine, imipramine, paroxetine, sertraline, group 5: nefazodone, nortriptyline, reboxetine, trimipramine, venlafaxine, group 6: maprotiline, mianserin, trazodone, group 7: clonazepam, phenytoin, group 8: amoxapine, buflomedil, clothiapine, codeine, dobutamine, group 9: buspirone, metoclopramide, metronidazole, ofloxacin, quetiapine, telmisartan, group 10: clozapine, levopromazine, loxapine, risperidone, thioproperazine, thioridazine and group 11: 7-aminoclonazepam, N-desalkylflurazepam, zuclopenthixol, chlorprothixene and haloperidol. Each of the 11 solutions described were prepared at concentrations of 2, 0.2, 0.04 and 0.004 μg/mL. These substances were selected according to their prevalence in the intoxications received and the availability of reference standards in the Chemistry Laboratory of INTCF-Madrid.

Preparation of blood samples

The blank blood used for sample preparation is routinely acquired by INTCF-Madrid from the Blood Transfusion Center from material that, due to certain characteristics cannot be used for medical purposes. A sample of blank blood is processed along with other samples to verify the absence of drugs in it.

The preparation of blood samples was carried out by spiking the analytes selected in human blood, at concentrations of 1, 2, 5, 10, 25, 50, 100, 250, 350, 500, 750 and 1000 ng/mL for the 56 drugs under study, using the previously prepared solutions.

Protein precipitation and removal of phospholipids

The preparation of samples based on protein precipitation and removal of phospholipids include the following steps: firstly, cellular lysis of 100 µL blood is performed to which 50 µL of the ZnSO4 0.1 M solution is added. After 5 min of resting, 50 µL of the internal standard are added, and protein precipitation is performed by addition and subsequent centrifugation (5 min at 14,000 rpm) of 650 µL of the 1 % (v/v) AF in ACN. The supernatant is loaded on a Phree Phospholipid plate from Phenomenex® (Torrance, CA, USA) and a positive pressure of 10 psi is applied for 5 min approximately. Then, the solution is evaporated to dryness and reconstituted with 200 µL of MP. Next, the solution is filtered by centrifugation (5 min at 14,000 rpm) in an Eppendorf tube with a 0.22 µm pore size membrane filter.

Instrument

The LC-MS/MS method used utilizes of an ExionLC UHPLC coupled to a Triple Quad 6500+ (QTRAP 6500+) from AB Sciex® (Framingham, MA, USA) consisting of a hybrid triple quadrupole enabling the third quadrupole to function as a linear ion trap (LC-Q-q-LIT). The LIT function provides several enhanced operating modes. Thus, spectra are rapidly acquired in a short period of time and are significantly more intense than spectra acquired using a comparable standard quadrupole method. As a result, sensitivity increases and spectral quality is improved.

Samples were analyzed using a new multiple reaction monitoring-information data acquisition-enhanced product ion (MRM-IDA-EPI) scanning technique that includes the 56 substances under study. For that purpose, we used Analyst® and MultiQuant® software from Sciex.

Parameters of high-resolution liquid chromatography

The liquid chromatograph includes a degasser, autosampler, column oven, and two binary pumps.

The MPs used are a mixture of 2 mM ammonium formate in water with 0.2 % (v/v) formic acid for MP A and 2 mM of ammonium formate in ACN with 0.2 % (v/v) formic acid for MP B. The concentration gradient begins with 10 % (v/v) of MP B during the first 0.5 min that increases linearly to 50 % of MP B at 12 min, 90 % of MP B at 14 min and up to 98 % at 15.5 min and then descends to initial conditions at 17.5 min and remains constant for 2.5 additional minutes. The total duration of the experiment is 19.8 min, maintaining a constant flow rate of 0.3 mL/min.

The sample injection volume is 2 µL, and the temperature of the autosampler is 12 °C.

Compound separation is performed using Kinetex 2.6 µm biphenyl 100 Å (100 × 2.1 mm) column from Phenomenex® (Torrance, CA, USA). Column oven temperature is 30 °C.

Parameters of mass spectrometry

A mass spectrometer consists of a hybrid triple quadrupole with two preliminary vacuum pumps and a compressed air and nitrogen source coupled to an IonDrive Turbo V ion source that uses the TurboIonSpray probe.

MS conditions are as follows: curtain gas, 35 psi; collision gas, intermediate; IS voltage, 5500 V; ion source temperature, 450 °C; ionization gas 1, 50 psi and ionization gas 2, 60 psi. The MS was set in positive ionization mode for all compounds. The ion trap works when signal intensity exceeds 6,000 counts per second (cps) for ions with an m/z ranging from 100 to 1,250.

Two transitions were used for the analysis of each analyte, whereas internal standards were analyzed using one transition. The MRM detection window is 60 s and the scan time is 0.4 s. The duration of the experiment was 19.8 min, with a duration of 0.8 s per cycle. Table 1 summarizes retention time, transitions, and specific characteristics of the 56 compounds, including declustering potential (DP), collision energy (CE), and collision cell exit potential (CXP).

Table 1:

LOD, LLOQ, measurement range, retention time and conditions of MS/MS for the 56 analytes analyzed on Sciex QTRAP 6500+.

Analyte LOD, ng/mL LLOQ, ng/mL Measurement range Retention time, min Q1 mass, Da Q3 mass, Da DP, V CE, V CXP, V Internal standard
7-Aminoclonazepam 2 5 5–750 6.41 286.1 222.22 70 29 10 Oxazepam-d5
121.11 60 35 10
Amitriptyline 5 10 10–1,000 12.19 278.12 91.15 60 15 10 Zolpidem-d6
191.14 60 15 10
Amoxapine 1 2 2–750 10.34 314.1 271.1 60 20 10 Oxazepam-d5
193.1 60 20 10
Bentazepam 1 5 5–1,000 9.69 297 269.1 60 35 10 Oxazepam-d5
166.1 60 35 10
Buflomedilo 1 1 1–1,000 7.84 308.2 237.1 60 50 10 Oxazepam-d5
195.1 60 50 10
Buspirone 1 2 2–750 9.18 386.3 122.1 41 25 10 Oxazepam-d5
265.2 41 25 10
Citalopram 2 10 10–1,000 10.37 324.94 109.1 60 35 10 Oxazepam-d5
262.1 91 27 10
Clobazam 1 1 1–1,000 12.95 301.07 259.18 76 27 10 Risperidona-d4
224.2 50 46 3
Clomipramine 2 10 10–1,000 13.09 315.16 86.1 60 50 10 Clomipramina-d3
242.07 60 50 10
Clonazepam 2 5 5–1,000 11.96 315.9 270 36 33 16 Oxazepam-d5
214.1 100 51 14
Chlordiazepoxide 1 5 5–1,000 8.11 300.16 282.1 60 35 10 Oxazepam-d5
227.18 60 35 10
Chlordiazepoxide 2 10 10–750 12.8 316.1 231.1 60 35 10 Risperidona-d4
221.1 60 35 10
Clotiapine 1 1 1–750 11.84 344.1 287 60 35 10 Oxazepam-d5
255.11 60 35 10
Clotiazepam 2 5 5–1,000 13.25 319.1 291.1 60 50 10 Risperidona-d4
218.17 60 50 10
Clozapine 1 10 10–750 8.19 327.1 270.1 60 35 10 Risperidona-d4
192.16 46 57 8
Codeine 1 2 2–1,000 4.6 300.3 215.2 66 33 12 Oxazepam-d5
165.09 120 55 8
Desalkylflurazepam 2 5 5–1,000 12.03 288.94 226.15 66 50 12 Oxazepam-d5
140 60 35 10
Diazepam 1 5 5–750 13.39 284.99 154 60 35 10 Oxazepam-d5
193.09 60 38 3
Dobutamine 1 1 1–750 5.93 302.2 137.1 36 31 4 Oxazepam-d5
107.08 36 31 4
Phenytoin 10 10 10–1,000 10.6 253.1 104.1 100 30 10 Zolpidem-d6
182.1 61 23 20
Flunitrazepam 1 10 10–750 12.91 314 268.1 60 35 10 Clomipramina-d3
239.14 65 49 3
Flurazepam 1 10 10–750 10.1 388 315.1 71 25 10 Clomipramina-d3
287.12 50 40 3
Haloperidol 1 1 1–1,000 11.04 376.15 165.12 111 37 22 Oxazepam-d5
123.05 61 51 14
Imipramine 1 10 10–1,000 11.79 281.2 86.1 76 25 14 Oxazepam-d5
193.1 76 25 14
Levomepromazine 1 2 2–1,000 12.34 329.2 100.1 60 35 10 Risperidona-d4
242.15 60 35 10
Lorazepam 2 5 5–750 11.2 320.95 274.98 60 50 10 Oxazepam-d5
229.17 50 41 10
Lormetazepam 1 2 2–750 12.79 334.97 288.97 60 35 10 Oxazepam-d5
177.19 50 59 8
Loxapine 1 2 2–500 10.93 328.08 271.07 51 31 16 Zolpidem-d6
193.19 41 59 10
Maprotiline 1 10 10–750 11.99 278.2 250.2 60 35 10 Zolpidem-d6
191.2 100 49 12
Metoclopramide 1 10 10–750 6.49 300.2 184.1 60 41 12 Oxazepam-d5
227.2 56 25 10
Metronidazol 1 2 2–750 3.51 171.81 128.1 60 20 10 Oxazepam-d5
82.03 60 20 10
Mianserin 1 2 2–1,000 10.48 265.12 208.04 60 35 10 Zolpidem-d6
193.2 60 35 10
Midazolam 1 2 2–750 9.87 325.98 291.1 60 35 10 Oxazepam-d5
249.06 60 35 10
Nefazodone 1 1 1–750 13.06 470.2 274 60 35 10 Oxazepam-d5
246.2 60 35 10
Nitrazepam 2 10 10–1,000 11.19 282.1 236.2 60 35 10 Salbutamol-d3
180.2 126 51 10
Nordiazepam 1 5 5–750 11.27 270.99 140 60 35 10 Oxazepam-d5
208.14 60 39 10
Nortriptyline 1 2 2–750 11.8 264.17 191.16 76 29 14 Oxazepam-d5
233.12 70 19 14
Ofloxacin 1 10 10–750 5.5 362.1 261.1 60 35 10 Oxazepam-d5
318.15 60 35 10
Oxazepam 5 10 10–750 10.94 287.03 269.2 56 21 32 Oxazepam-d5
241.11 96 33 14
Paroxetine 2 25 25–1,000 11.37 330.2 192 91 39 16 Zolpidem-d6
135.07 91 39 16
Prazepam 1 2 2–750 14.91 325.07 271.14 60 35 10 Risperidone-d4
165.13 60 35 10
Quetiapine 1 1 1–750 9.54 384.13 221.14 96 49 12 Oxazepam-d5
253.06 60 35 10
Reboxetine 5 10 10–750 10.29 314.17 176.1 126 43 26 Oxazepam-d5
91.09 40 39 10
Risperidone 1 5 5–1,000 8.49 411 191.3 56 27 12 Risperidone-d4
163.1 56 27 12
Sertraline 1 10 10–1,000 12.59 306.1 275.1 66 17 14 Zolpidem-d6
159.02 30 33 10
Telmisartan 1 5 5–750 12.84 515.2 497.27 100 50 12 Oxazepam-d5
276.2 60 35 10
Temazepam 2 10 10–750 12.52 301.2 255.2 101 33 8 Salbutamol-d3
283.18 76 19 10
Tetrazepam 5 10 10–750 11.3 288.93 225 60 35 10 Oxazepam-d5
197.2 106 43 10
Thioproperazine 2 5 5–1,000 11.3 447 141.2 61 55 10 Risperidone-d4
319.06 61 55 10
Thioridazine 1 5 5–1,000 14.31 371.1 126.2 106 33 10 Clomipramina-d3
258.11 106 33 10
Trazodone 1 5 5–750 9.3 372.09 176.13 60 35 10 Zolpidem-d6
148.04 81 48 10
Triazolam 1 5 5–750 11.95 343.1 308.2 65 39 3 Oxazepam-d5
239.2 60 35 10
Trimipramine 1 2 2–750 12.43 295.2 100.1 60 35 10 Oxazepam-d5
208.15 60 35 10
Venlafaxine 1 10 10–750 8.09 278 260.3 60 20 10 Oxazepam-d5
121.05 60 20 10
Zolpidem 5 10 10–750 8.5 308.1 235.2 60 20 10 Zolpidem-d6
263.13 60 20 10
Zuclopentixol 10 25 25–750 11.8 401.11 356.18 60 20 10 Zolpidem-d6
271.15 60 20 10
Clomipramine-d3 – – – 13.09 318 89.2 60 35 10
Ketamine-d4 – – – 6.53 241.9 129.1 60 30 10
Oxazepam-d5 – – – 10.94 292.13 246.1 96 21 10
Pseudoephedrine-d3 – – – 3.4 169.1 151 60 20 10
Risperidone-d4 – – – 8.49 415.24 195.14 60 35 10
Salbutamol-d3 – – – 2.54 243.04 151.12 56 27 20
Tramadol-d3 – – – 6.84 268 58 60 35 10
Zolpidem-d6 – – – 8.5 314.32 235.2 61 47 4

The following parameters were evaluated for substance verification: presence of a peak at the appropriate retention time; existence of the two MRM transitions per substance; and identification of substance spectrum through the use of a “spectral library” of compounds.

Acceptance criteria

The LOD of each analyte was established by analysing different drugs at concentrations of 1, 2, 5, 10, 25 and 50 ng/mL. The lowest concentration with a signal:noise ratio ≥3:1 was established as the LOD. The LLOQ was established using the same method, but with a signal:noise rate ≥10:1. For such purpose, samples were analyzed in triplicate.

With regard to calibration, the linearity of all substances was evaluated from 1 ng/mL (CAL 1) to 1,000 (CAL 12) ng/mL. The quadratic regression model was used for all substances, except for metoclopramide, 7-aminoclonazepam and zuclopenthixol, which followed a linear regression model. In line with previous studies [8, 9], the acceptance criteria for all calibration lines included a coefficient of determination (r2) > 0.99; a coefficient of variation (CV) <±20 % at all data points along the curve; and a calibration curve composed of at least seven points.

Sample analysis

To evaluate the application of the new sample preparation method, 11 blood samples were analyzed with the new method on a QTRAP 6500+ analyzer. These cases had been previously analyzed using traditional sample preparation methods, involving at least a SP and LLE, and using LC-DAD, GC-MS, LC-MS/MS and immunoassay techniques. For some substances, special extractions and/or techniques were also used, including GC-MS/MS and LC-HR-MS (Q Exactive Orbitrap). Finally, the results obtained with traditional extractions and methods were compared against the results of the new method under study.

Results

Table 1 shows results for LOD, LLOQ and measuring range for all the substances analyzed on QTRAP 6500+. All outlined substances met our acceptance criteria.

Ten of the eleven cases selected were positive, whereas a case was negative. Six of the eleven samples analyzed with the new method were positive. In contrast, five samples were negative, because the drugs in the four positive cases (paracetamol, naproxen, metamizole and benzoylecgonine) were not included in the new method. In the six positive cases, the two methods detected the same substances, except for sertraline in case 11. In contrast, the new method detected lorazepan in case 1. Concentrations were calculated using the calibration curve of each drug and the most appropriate internal standard, as detailed in Table 1. The results obtained were comparable, except for quetiapine in case 1 and diazepam in case 11. Results are shown in Table 2.

Table 2:

Comparison of the substances detected by the different techniques and methods.

Case number Traditional method and immunoassay, LC-DAD, GC-MS and LC-MS/MS analysis New method and QTRAP 6500+ analysis
1 Lorazepam ND Lorazepam 15.4 ng/mL
Quetiapine 60 ng/mL Quetiapine 2.6 ng/mL
2 Lorazepam 50 ng/mL Lorazepam 72.4 ng/mL
5 Codeine 13.3 ng/mL Codeine 18.1 ng/mL
9 Diazepam <10 ng/mL Diazepam <5 ng/mL
10 Diazepam 40 ng/mL Diazepam 49.2 ng/mL
11 Metoclopramide <100 ng/mL Metoclopramide 40.7 ng/mL
Haloperidol 8 ng/mL Haloperidol 1 ng/mL
Trazodone 300 ng/mL Trazodone 187 ng/mL
Diazepam 200 ng/mL Diazepam 31.9 ng/mL
Sertraline 100 ng/mL Sertraline ND

  1. ND, not detected.

Discussion

A new sample preparation method was developed based on protein precipitation, removal of phospholipids, and the use of more sensitive techniques, such as LC-Q-q-LIT. Comparable results were obtained for 56 substances with respect to the traditional method, as the two methods virtually detected the same substances. However, this is a preliminary study. A more thorough validation process that evaluates the extraction performance, carryover effect, and matrix effect in all the drugs and internal standards included in this study. Further research is also needed to evaluate drug quantification using the new methodology. The main advantage of the new method is the reduction of time and costs, as compounds of different characteristics can be detected in a single sample, with a high sensitivity and selectivity, and in a shorter time. These characteristics are a considerable advantage, especially in clinical samples.

A limitation of this study was the inability to detect sertraline, and the limited number of substances analyzed. However, this is a good starting point for the future implementation of this new method, especially in clinical samples such as cases of chemical submission, which require rapid testing and a high sensitivity and specificity.

Corresponding author: Alba M. Rodrigo Valero, Departamento Madrid, Servicio de Química, Instituto Nacional de Toxicología y Ciencias Forenses (INTCF), Calle José Echegaray, 4, 28232, Las Rozas, Madrid, Spain, E-mail:

  1. Research ethics: This human research study complies with all national regulations, institutional policies and principles of the Declaration of Helsinki, having been approved by the Medicine Research Ethics Committee of the Guadalajara health area (CEIm).

  2. Informed consent: Not applicable.

  3. Author contributions: The authors have accepted responsibility for the entire content of this manuscript and approved its submission.

  4. Competing interests: The authors state no conflict of interest.

  5. Research funding: The study was funded by the José Luis Castaño-SEQCML Foundation as aid for young professionals in 2021 research projects.

  6. Data availability: The raw data can be obtained on request from the corresponding author.

  7. Article Note: The original article can be found here: https://doi.org/10.1515/almed-2023-0115.

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Received: 2023-08-25
Accepted: 2023-09-13
Published Online: 2023-11-23

© 2023 the author(s), published by De Gruyter, Berlin/Boston

This work is licensed under the Creative Commons Attribution 4.0 International License.

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https://doi.org/10.1515/almed-2023-0154
Keywords for this article
screening; removal of phospholipids; mass spectrometry; protein precipitation; blood
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