Mass spectrometry for the quantification of drugs in biosamples

C H A P T E R

3 Mass spectrometry for the quantification of drugs in biosamples Rafael Lindena,*, Marina Venzon Antunesa, Jose Luiz Costab a

Laboratory of Analytical Toxicology, Institute of Health Sciences, Universidade Feevale, Novo Hamburgo, RS, Brazil; bFaculty of Pharmaceutical Sciences, University of Campinas, SP, Brazil *Corresponding author. E-mail: [email protected]

Abstract This chapter presents an overview on the use of mass spectrometry assays for drug measurement in biosamples. Drug measurement in biological specimens, particularly in the context of therapeutic drug monitoring (TDM), requires the availability of robust and well-validated laboratory assays in order to render clinically useful information. Among several available analytical methods, mass spectrometry measurement systems, preferentially coupled to liquid chromatography, are currently the mainstay of assays for TDM. These methods usually present the required sensitivity for measurement of drug concentrations in small specimens, including dried blood spots, as well as the required specificity for clinical applications. There are numerous reports on the use of mass spectrometry coupled to both gas and liquid chromatography for many important classes of drugs of relevance for TDM. Particularly, liquid chromatography tandem mass spectrometry is currently the mainstay of comprehensive drug measurement in biosamples, being a fundamental resource for laboratories working in the field of TDM.

3.1 Introduction Drug measurement in biological specimens, particularly in the context of therapeutic drug monitoring (TDM), requires the availability of robust and well-validated laboratory assays in order to render clinically useful information. Among several available analytical methods, mass spectrometry measurement systems, preferentially coupled to liquid chromatography, are currently the mainstay of assays for TDM. These methods usually present the required sensitivity for measurement of drug concentrations in small specimens, including dried blood spots (DBS), as well as the required specificity for clinical applications. DBS samples are a theme of growing interest in the field of TDM due to potential advantages such as minimally invasive sampling, high analyte stability, possibility of self-sampling by patients, and ease of transportation [1e3]. This particular specimen for drug measurement also requires specific

Methods of Therapeutic Drug Monitoring including Pharmacogenetics https://doi.org/10.1016/B978-0-444-64066-6.00003-4

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Ó 2020 Elsevier B.V. All rights reserved.

48

3. Mass spectrometry for the quantification of drugs in biosamples

and extensive validation in order to allow extrapolation of measured concentrations to plasma or serum levels, particularly considering the influence of the hematocrit [3]. In this context, the present chapter presents an overview of mass spectrometry as applied to the determination of drug and metabolites in biological samples, also presenting representative published applications of these assays.

3.2 Gas chromatographyemass spectrometry Gas chromatography (GC) is one of most important techniques of analytical chemistry and is also widely used in analytical toxicology. It is a well-established analytical technique (origin dates back to the 1950s), which allows the separation of a large number of volatile and thermostable substances. One of the most important characteristics of GC is the high separation efficiency, usually higher than liquid chromatography, especially with the use capillary columns (internal diameter < 0.32 mm). This high efficiency allows the separation of several substances present in biosamples, including drugs and possible endogenous interferents, an important feature in the analysis of complex specimens, such as biological matrices. The technology used in the development of GC columns has produced durable columns, with high thermal stability and low stationary phase bleeding, resulting in symmetrical chromatographic peaks and with high reproducibility of retention times. Another important feature of GC is the separation in gas phase, requiring low flow of an inert carrier gas (e.g., hydrogen or helium), which also allows direct coupling to mass spectrometry systems, combining a powerful separation technique to one of most important identification techniques available [4,5]. The simpler gas-phase separation allowed the development of the gas chromatography coupled to mass spectrometry (GC-MS) instruments much earlier than liquid chromatographyemass spectrometry (LC-MS) systems, and had become the gold standard in drug analysis since the 1980s. The major limitation of GC-MS lies in the fact that the technique only allows the analysis of hydrophilic, thermolabile, and nonvolatile analytes after an extensive (and sometimes costly) sample preparation process. Substances with polar functional groups such as amines, alcohols, and carboxylic acids (frequently present in drugs, and mostly in drugs metabolites) have higher boiling points (and lower vapor pressure) and cannot be directly analyzed by GC. To overcome this problem, the addition of a derivatization step is necessary at the end of the sample preparation procedure, before injection into the chromatograph. The choice of derivatization reagent depends on the physical and chemical properties of the target analytes and the instrument characteristics. The derivatized products have to be stable (at least for a batch running time, e.g., 12e24 h). Furthermore, as not all reagents can be injected directly into an analytical system, an excess derivatization reagent may need to be removed prior to analysis [6]. Silanization of hydroxyl groups with reagents such as N-tert-butyldimethylsilylN-methyltrifluoroacetamide (MTBSTFA) or N,O-bis(trimethylsilyl)trifluoroacetamide (BSTFA) containing 1% of trimethylchlorosilane (TMCS) is frequently used in drugs analyses [7]. In the analytical toxicology field, the screening procedures published by Maurer, Pfleger, and Weber use acetylation with acetic anhydride and pyridine, and have been applied to over 10,000 potential harmful substances and metabolites [8]. Perfluoroacylated acylation reagents, such as trifluoroacetic acid anhydride (TFAA), pentafluoropropionic acid anhydride (PFPA), and heptafluorobutyric acid anhydride (HFBA), are used to form stable and volatile derivatives

3.2 Gas chromatographyemass spectrometry

49

with alcohols, amines, and phenols groups [9,10]. PFPA and HFBA should be used with an acid scavenger, to help drive the reaction to completion and to prevent chromatographic column damage from acidic by-products of the derivatization reaction. Trimethylanilinium hydroxide (TMAH) can be used to flash methylation in injection port of GC-MS instrument [11]. To be analyzed in the mass spectrometer, the compounds that elute from the chromatographic column must be converted into charged particles. Electron ionization (EI) is the simplest and most commonly used ionization mode to the analysis of drugs by GC-MS. In this ion source, a high-energy (generally 70 eV) electron beam is emitted by a heated filament; these electrons reach the drug molecules eluting from the column, removing an electron and producing the corresponding cation (molecular ion). A positive electrical potential will direct the produced cations into focalization lens inside the mass spectrometer. The energy transmitted by the electron beam to the molecule during the ionization process frequently leads to significant fragmentation of molecular ion. The fragmentation pattern of a substance in EI is very reproducible, even when obtained in instruments from different manufacturers, allowing the computer-assisted comparison of sample mass spectrum commercially available mass spectra libraries, some containing data from thousands of substances. Comparison of mass spectra in GC-MS is one of the most important tools for identification of drugs and metabolites in toxicological analyzes. A disadvantage of the significant fragmentation produced in EI is the fact that, for most substances, the molecular ion is not present in the spectrum, making the molecular mass determination unfeasible. Chemical ionization (CI) is another relevant mode of ionization in GC-MS analysis. In CI, the analyte reacts with an ionized reagent gas (e.g., methane, ammonia, isobutane) producing the correspondent molecular ion by different mechanisms (such as adducts formation, electron or proton transfer). The most important characteristic of CI is the production of spectra with lower or no fragmentation (comparing to EI), where the molecular ion can be easily determined. This feature is interesting to the evaluation of molecular mass of a substance, and is interesting in instruments with triple quadrupole mass analyzer (for GC-MS/MS multiple reaction monitoring [MRM] mode analysis) [12]. Several mass analyzers are commercially available, all of them are used to separate produced ions according to the mass-to-charge ratio (m/z). The quadrupole mass analyzer is the most frequently used in GC-MS instruments. This analyzer is composed by four rods arranged in parallel and opposite arrangement. Two varying electrostatic fields, one direct current and one at varying radiofrequency are applied at right angles to each other via the four rods of the quadrupole, creating a resonance frequency for each m/z value in the mass spectrum. The full mass range is scanned (scan mode) by varying the resonant frequency of the quadrupole such that ions of sequential m/z transit the analyzer and reach the detector. The quadrupole can also be set to operate with fixed resonant frequency, so that only specific m/z can transit the analyzer and be detected. This analyzing mode is called selected-ion monitoring (SIM) mode, and is useful to measure known substances present in a sample. Quadrupole instruments provide unitary mass resolution, which is suitable for most drug analyses by GC-MS [4]. In general, the scan mode was used for screening of unknown substances, while the SIM mode was used for the quantitative analyses of substances known to be present in the samples, or when greater sensitivity and selectivity were required. This distinction was made because the scanning speed of older instruments was low, leading to the loss of ions during the mass scanning process, resulting in lower sensitivity. The current instruments have scan speeds

50

3. Mass spectrometry for the quantification of drugs in biosamples

greater than 12,000 m/z per second, allowing quantitative analyses with sensitivity equivalent to those obtained in SIM mode. In triple quadrupole mass analyzers (QQQ), three quadrupoles are organized in series, allowing high-selective and sensitive analysis. The first (Q1) and the third (Q3) quadrupoles can operate as described above, operating in scan or SIM mode. The second quadrupole (Q2) is not used for m/z separation, instead it is used to produce fragment ions by collisioninduced dissociation (CID). In this process, the ions from Q1 are fragmented by collisions with inert gas (nitrogen or argon), and these fragments can be scanned in Q3. There are several ways of operating a QQQ mass spectrometer, the most common in drug analysis is set the Q1 in SIM mode (to the specific m/z of the substance), fragment the drug ion in Q2 and use Q3 also in SIM mode, but filtering m/z from specific fragments produced in Q2. This operating mode is called MRM and provides high sensitivity analysis, since both quadrupoles are used as mass filters, removing undesirable ions from the system.

3.3 Liquid chromatographyemass spectrometry The LC-MS systems are nowadays the most important analytical tool for drug analysis in biological samples. In contrast to GC-MS, LC-MS has minor analyte limitations, allowing the analysis of polar, thermolabile, and high-molecular-weight compounds, without a derivatization step. Compounds such as phase II metabolites, antibiotics, amino acids, and peptides can be easily measured with high sensitivity [13]. The sample preparation step in LC-MS can be simplified when compared to GC-MS, but this step of the analysis cannot be totally eliminated, since the large amount of interferents present in the sample extract can contaminate the system and, mainly, due to the effect matrix that may lead to inaccurate or false-negative results in qualitative analyzes. In some (rare) situations, a derivatization step can be used [14,15]. Commercially available instruments allow sample preparation procedures to be done online with the LC-MS system, providing high throughput of samples. One important disadvantage of LC-MS is still the considerable cost of instrument and supplies (high-purity organic solvents, gases, columns, etc.). Although some authors consider the matrix effect as a disadvantage of the LC-MS, this phenomenon is well known nowadays, and several alternatives to evaluate or even circumvent it are already published in the literature. Electrospray ion source (ESI) and atmospheric-pressure chemical ionization (APCI) are the most commonly used ionization modes in drug analysis. In ESI mode, the mobile phase containing eluted analytes is sprayed into the source by a metallic capillary held at a high electric potential (usually between 2 and 5 kV), with coaxial nebulizer gas flow (nitrogen). At the tip of the capillary, positive or negative ions are separated from their counterions. The isolated ions are repelled by the capillary and attracted by a metallic cone at instrument entrance. During this process, charged droplets are formed and when dried, the excess of positive or negative charges in the droplets produce repulsion and lead to the droplet breakup, expulsing the analyte with a proton from solvent, or loss of one in negative mode [4]. Since the mobile phase plays an important role in the LC-MS ionization process, its characteristics must be highlighted. Only volatile chemical reagents can be used to prepare the mobile phase, since it has to be evaporated at the ionization source. Thus, salts, acids, and bases commonly used in HPLC (e.g., phosphoric acid, phosphate buffer) cannot be used

3.4 Applications

51

when the instrument is coupled to the mass spectrometer. The main additives used are formic acid, acetic acid, ammonium formate, ammonium acetate, and ammonium hydroxide. As the mobile phase needs to be evaporated, the use of small flow rates, in the order of 0.5 mL/min (or less), favors the ionization process in ESI mode. To work with these flow rates, the use of low dimension columns are desirable. A typical LC-MS column has a length of less than 100 mm, an inner diameter of less than 4 mm, and a particle size of less than 4 mm. The APCI mode has almost the same hardware configuration of ESI, but with the introduction of a corona discharge needle. However, the APCI ionization process is more similar to GC-MS CI than to ESI. In this case, the ionization will occur in gas phase, and the reagent ions that promote the analyte’s ionization are produced from mobile phase constituents (by contact with the corona discharge needle). Usually, APCI is suitable to nonpolar substances such as steroids, and less sensitive to matrix effect than ESI. Matrix effect is a well-known characteristic of LC-MS ionization and can be defined as the alteration in response due to the presence of coeluting compounds that may increase (ion enhancement) or reduce (ion suppression) ionization of the analyte. Different approaches have been published in the literature trying to minimize the matrix effect in bioanalysis [16e19]. Quadrupole mass analyzers are also used in LC-MS, mainly in their triple quadrupole configuration. The use of single quadrupole equipment is limited in drug analysis, due to low selectivity and sensitivity. As previously described, the QQQ instruments are the best choice for quantitative analysis of drugs and metabolites in biological samples. In the LC-MS/MS system, the combination of ESI (or APCI) with QQQ mass analyzer provides better results than GC-MS/MS, since the LC-MS/MS ionization process is mild, with little or no fragmentation at the ionization source. Thus, the intact molecule of the analyte may be filtered at Q1 to be then fragmented at Q2, producing ions of higher m/z ratio, less subject to interference. In recent years, the use of time of flight (TOF) and Orbitrap mass analyzers has been gaining ground and are becoming important tools in the analysis of drugs and metabolites in biological samples. The main advantage of these analyzers is to provide mass measurements with high resolution and accuracy. While quadrupole-type analyzers provide unit mass measurements, TOF and Orbitrap analyzers are able to measure the mass up to the fourth (or fifth) decimal point. The most common configuration is to quadrupole and high resolution mass analyzers in tandem. As it happens to QQQ, QTOF or Q-Orbitrap equipment can be used in different scanning/selecting modes and are important tools for untargeted drug screening and drug metabolite identification [20e22]. They are also useful for quantitative analysis, sometimes providing limits of detection/quantification equivalent to QQQ instruments [23,24]. The major disadvantage of high-resolution mass spectrometers is the elevated cost of instruments, much higher than QQQ.

3.4 Applications Numerous applications of mass spectrometricebased analytical methods in the context of TDM were reported in the literature, being reported for a large diversity of therapeutic classes of drugs, such as antifungals, antibiotics, antiretrovirals, immunosuppressants, antiepileptics, antineoplastic, and several central nervous acting drugs, such as antidepressants and antipsychotics. The majority of these assays were based on LC-MS/MS, with some reports of GC-MS use. Table 3.1 summarizes an overview of these methods for drug classes relevant in the context of TDM.

TABLE 3.1 Overview of mass spectrometric assays for various drug classes. Sample

Sample preparation technique

Run time (min)

Analytical range

Reference

Itraconazole

Plasma

YMC hydrosphere C18 (50
2.0 mm; 3 mm)

1.5

0.001 to 0.5 mg/mL

[25]

Fluconazole Itraconazole Hydroxyitraconazole Posaconazole Voriconazole Voriconazole-N-oxide Caspofungin Anidulafungin

LC-MS/MS (EIS)

Acquity C18 (30
2.1 mm, 1.7 mm)

7.0

0.1 to 50 mg/mL fluconazole 0.02 to 10 mg/mL itraconazole/ hydroxyitraconazole/ posaconazole voriconazole 0.01 to 5.0 mg/mL voriconazole-N-oxide 0.06 to 30 mg/mL caspofungin 0.1 to 12 mg/mL anidulafungin

[26]

Semiautomated 96-well protein precipitation

LC-MS/MS (APCI) positiveion mode

Polaris C18A (50
2.0 mm; 5 mm)

4.0

0.005 to 5.0 mg/mL

[27]

Plasma

Protein precipitation and automated SPE using Waters Oasis MCX 10 mg 96-well extraction cartridges

LC-MS/MS (EIS) positive-ion mode

Halo C18 (50
2.1 mm; 2.7 mm)

1.05

0.005 to 5.0 mg/mL

[28]

Fluconazole Voriconazole Ketoconazole Posaconazole Itraconazole Hydroxyitraconazole

Serum

Online preparation C18eP-XL (50
0.5 mm) TurboFlow column.

LC-MS/MS (APCI) positiveion mode

Gemini C6 phenyl (150
3.0 mm; 3 mm)

12.0

0.05 to 5.0 mg/mL itraconazole/ hydroxyitraconazole/ posaconazole 0.1 to 10.0 mg/mL voriconazole/fluconazole

[29]

Itraconazole Voriconazole Posaconazole

Plasma

Protein precipitation

LC-MS (EIS) positive-ion mode

C18 Atlantis T-3 (150
4.6 mm; 5 mm)

13.0

0.031 to 8.0 mg/mL itraconazole/posaconazole 0.039 to 10 mg/mL voriconazole

[30]

Drug class

Instrumentation

Column

Protein precipitation

LC-MS/MS (EIS) positive-ion mode

Plasma

Protein precipitation

Posaconazole

Plasma

Posaconazole

Antifungals

Voriconazole

Plasma

Protein precipitation

LC-MS/MS (EIS) positive-ion mode

Only Security guard Cartridge C18 (4
3.0 mm)

2.0

0.06 to 20 mg/mL

[31]

Voriconazole

Serum

Protein precipitation

LC-MS/MS (EIS) positive-ion mode

Kinetex C18 (100
3 mm; 2.6 mm)

4.0

0.1 to 10 mg/mL

[32]

Posaconazole

DBS

Liquideliquid extraction

LC-MS/MS (EIS) positive-ion mode

Kinetex C18 (50
2.1 mm; 2.6 mm)

1.0

0.005 to 5 mg/mL

[33]

Voriconazole Fluconazole Posaconazole

DBS

Liquideliquid extraction

LC-MS/MS (EIS) positive-ion mode

HyPURITY Aquastar C18 (50
2.1 mm; 5 mm)

3.6

0.1 to 10 mg/mL voriconazole/ posaconazole 0.5 to 100 mg/mL fluconazole

[34]

Fluconazole Itraconazole Hydroxyitraconazole Voriconazole Posaconazole

Plasma

Protein precipitation

LC-MS/MS (EIS) positive-ion mode

C18 Hypersil gold (50
2.1 mm; 3 mm)

15.0

0.1 to 12 mg/mL

[35]

Iodiconazole

Plasma

Liquideliquid extraction

LC-MS/MS (EIS) positive-ion mode

Zorbax SB-C18 (100
2.1 mm; 3.5 mm)

3.0

0.1 to 20 ng/mL

[36]

Itraconazole Hydroxyitraconazole

Plasma

Automated liquid eliquid extraction 96-well plate

LC-MS/MS (EIS) positive-ion mode

YMC C18-A (50
4.0 mm i.d)

2.0

0.002 to 0.5 mg/mL itraconazole 0.004 to 1.0 mg/mL hydroxyitraconazole

[37]

Fluconazole

Plasma

Protein precipitation

LC-MS/MS (EIS) positive-ion mode

XTerra C18 (100
2.1 mm, 3.5 mm)

5.5

0.1 to 10 mg/mL

[38]

Fluconazole Itraconazole Ketoconazole Voriconazole

Plasma

Protein precipitation and online SPE using Waters Oasis HLB (20
2.1 mm, 25 mm)

LC-MS/MS (EIS) positive-ion mode

Allure PFP propyl (50
2.1 mm; 5 mm)

3.0

0.0014 to 10 mg/mL

[39]

(Continued)

TABLE 3.1 Overview of mass spectrometric assays for various drug classes.dcont'd Drug class

Sample

Sample preparation technique

Fluconazole Itraconazole Hydroxyitraconazole Voriconazole Posaconazole

Plasma

Daptomycin

Instrumentation

Column

Protein precipitation

LC-MS/MS (EIS) positive-ion mode

HyPURITY Aquastar C18 (50
2.1 mm; 5 mm)

Plasma

Protein precipitation

UPLC-QToF premier (EIS) positive-ion mode

Gentamicin (C1; C1a; C2; C2a; C2b)

Plasma Serum

Protein precipitation

Vancomycin

Plasma

Vancomycin

Run time (min)

Analytical range

Reference

3.6

0.5 to 200 mg/mL fluconazole 0.1 to 5.0 mg/mL itraconazole/ hydroxyitraconazole 0.1 to 10 mg/mL posaconazole 0.05 to 10 mg/mL voriconazole

[40]

Acquity C18 (100
2.1 mm, 1.7 mm)

3.5

0.01 to 10 mg/mL

[41]

LC-MS/MS (EIS) positive-ion mode

XSelect HSS PFP (100
2.1 mm; 2.5 mm)

16.0

0.1 to 12 mg/mL

[42]

Protein precipitation

LC-MS/MS (EIS) positive-ion mode

Acquity UPLC BEH HILIC (100
2.1 mm; 1.7 mm)

5.0

0.6 to 100 mg/mL

[43]

Serum

Protein precipitation

LC-MS/MS (EIS) positive-ion mode

Fortis C8 (100
2.1 mm, 3 mm)

21.0

1.06 to 84 mg/mL

[44]

Teicoplanin (A2-1, A2-2,3; A2-4,5; A3-1)

Plasma

Dilution

LC-MS/MS (EIS) positive-ion mode

Cadenza HS-C18 (75
3.0 mm; 3 mm)

6.5

1.0 to 50 mg/mL

[45]

Teicoplanin (A2-1, A2-2,3; A2-4,5; A3-1)

Plasma of neonates

Protein precipitation

LC-MS/MS (EIS) positive-ion mode

Acquity UPLC BEH C18 (100
2.1 mm; 1.7 ìm)

9.0

0.025 to 6.4 mg/mL

[46]

Linezolid

Dried blood spot

Liquideliquid extraction

LC-MS/MS (EIS) positive-ion mode

Zorbax Eclipse Plus C18, (50
21 mm; 18 mm)

22

1 to 100 mg/mL

[47]

Antibiotics

Amikacin Kanamycin

Serum

Protein precipitation

LC-MS/MS (EIS) positive-ion mode

HyPURITY C18 (5.0
2.1 mm; 3 mm)

6.0

0.25 to 25 mg/mL amikacin 0.1 to 25 mg/mL kanamycin

[48]

Amikacin Gentamicin Vancomycin

Plasma of neonates

Protein precipitation

LC-MS/MS (EIS) positive-ion mode

HyPURITY Aquastar (100
2.1 mm; 5 mm)

7.5

0.3 to 50 mg/mL amikacin/ gentamicin 1.0 to 100 mg/mL vancomycin

[49]

Daptomycin Amikacin Gentamicin Rifampicin

Plasma

Protein precipitation

LC-MS (EIS) positive-ion mode

Synergy 4u HydroRP 80A (250
4.6 mm)

18.0

2.34 to 130 mg/mL amikacin 0.63 to 40 mg/mL gentamicin/ rifampicin 1.56 to 130 mg/mL daptomycin

[50]

Daptomycin Ceftaroline Linezolid Rifampicin

Plasma

Protein precipitation Online SPE (POROS R1/20, 30
2.1 mm)

LC-MS/MS (EIS) positive-ion mode

Phenyl hexyl Luna (50
2.0 mm; 5 mm)

3.0

0.20 to 40 mg/mL ceftaroline 0.50 to 100 mg/mL daptomycin 0.04 to 8.0 mg/mL linezolid 0.1 to 20 mg/mL rifampicin/ 25-O-Desacetylrifampicin

[51]

Amoxicillin Ampicillin Cefazolin Cefuroxime Ceftazidime Clavulanic acid Piperacillin Tazobactam Meropenem

Serum

Protein precipitation

LC-MS/MS (EIS) positive-ion mode

Acquity UPLC BEH C18 (100
2.1 mm; 1.7 mm)

5.5

1.50 to 100 mg/mL piperacillin 0.50 to 100 mg/mL others

[52]

Amoxicillin Ampicillin Cefadroxil Cefazolin Cefepime Ceftazidime Cefuroxime Flucloxacillin Linezolid Meropenem Phenoxymethylpenicillin

Plasma

SPE (Oasis MCX m-elution 96 plate)

LC-MS/MS (EIS) positive and negative-ion mode

Acquity HSS T3 (50
2.1 mm; 1.7 mm)

4.0

0.43 to 51.05 mg/mL amoxicillin 0.58 to 70.05 mg/mL ampicillin 0.05 to 6.04 mg/mL cefadroxil 0.61 to 73.01 mg/mL cefazolin 0.18 to 21.53 mg/mL cefepime 0.76 to 90.81 mg/mL ceftazidime 0.48 to 57.69 mg/mL cefuroxime 0.08 to 9.11 mg/mL

[53]

(Continued)

TABLE 3.1 Overview of mass spectrometric assays for various drug classes.dcont'd Drug class

Sample

Sample preparation technique

Instrumentation

Column

Run time (min)

Piperacillin Tazobactam

Piperacillin Tazobactam Linezolid Meropenem Ceftazidime

DBS VAMS

Liquideliquid extraction

LC-MS/MS (EIS) positive-ion mode

Kinetex C18 (100
4.6 mm; 2.6 mm)

5.5

Amoxicillin Amikacin Ampicillin Cefepime Ceftazidime Ceftriaxone Clarithromycin Clavulanic acid Daptomycin Imipenem Levofloxacin Linezolid Meropenem Moxifloxacin Piperacillin Sulbactam Tazobactam Teicoplanin Tigecycline Tobramycin Vancomycin

Urine Serum Cerebrospinal fluid Bronchial aspirations

Serum: Protein precipitation Bronchial asp: Liquefaction Others: Dilution

LC-MS/MS (EIS) positive and negative-ion mode

Acquity UPLC BEH C18 (100
2.1 mm; 1.7 mm)

6.0

Analytical range flucloxacillin 0.05 to 5.94 mg/mL linezolid 0.17 to 20.06 mg/mL meropenem 0.06 to 7.28 mg/mL phenoxymethylpenicillin 0.32 to 38.06 mg/mL piperacillin 0.24 to 28.24 mg/mL tazobactam 3.12 to 200 mg/mL piperacillin/ceftazidime 0.62 to 40 mg/mL tazobactam/ meropenem/linezolid 0.1 to 5 mg/mL 0.1 to 5 mg/kg for bronchial aspiration matrix

Reference

[54]

[55]

Vancomycin Teicoplanin Daptomycin Colistin

Plasma

Protein precipitation

LC-MS/MS (EIS) positive-ion mode

Kinetex C18 (50
2.1 mm; 2.6 mm)

10.0

0.5 to 100. mg/mL vancomycin/daptomycin 0.13 to 54 mg/mL colistin 0.14 to 63.8 mg/mL teicoplanin

[56]

Moxifloxacin

Plasma Plasma ultrafiltrate Cerebrospinal Fluid

Protein precipitation

LC-MS/MS (EIS) positive-ion mode

Electron HyPURITY C18 (50
2.1 mm; 5 mm)

2.5

0.05 to 5.0 mg/mL

[57]

Oxytetracycline Tetracycline Chlortetracycline

Urine

SPE (Oasis HLB, 6 cm3, 200 mg)

UPLC-QToF-MS (EIS) positive-ion mode

Acquity C18 (100
2.1 mm, 1.7 mm)

6.5

0.5 to 10 mg/mL

[58]

Colistin A,B Colistin Methanesulfonate

Plasma Urine

SPE (Oasis HLB 30 mg, 1 mL)

LC-MS/MS (EIS) positive-ion mode

C18 XBridge (150
2.1 mm 5 mm)

3.8

0.024 to 6.144 Colistin A 0.015 to 3.856 Colistin B 0.029 to 7.492 Colistin Methanesulfonate A 0.010 to 2.508 Colistin Methanesulfonate B

[59]

Piperacillin Benzylpenicillin Flucloxacillin Meropenem Ertapenem Cephazolin Ceftazidime

Plasma

Protein precipitation

LC-MS/MS (EIS) positive-ion mode

C18 (50
2.1 mm; 2.6 mm)

7.0

0.1 to 50 mg/mL

[60]

Mycophenolic acid

Plasma

Protein precipitation

LC-MS/MS (EIS) negative-ion mode

Kinetex C18 (30
4.6 mm, 2.6 mm)

4.5

0.5 to 30 mg/mL

[61]

Mycophenolic acid

Plasma Oral fluid

Protein precipitation for total and oral fluid mycophenolic; ultrafiltration for free drug

LC-MS/MS (EIS) positive-ion mode

Allure PFP propyl (100
2.1 mm, 5 mm)

5.0

0.1 to 51.2 mg/mL total 2.0 to 256 mg/mL free drug and oral fluid

[62]

Immunosuppressants

(Continued)

TABLE 3.1 Overview of mass spectrometric assays for various drug classes.dcont'd Sample preparation technique

Instrumentation

Column

Run time (min)

Analytical range

Reference

DBS

Liquid extraction and SPE (Oasis HLB 1cc, 10 mg)

LC-MS/MS (EIS) positive-ion triple quadrupole mode

Nova-Pak C18 (10
2.1 mm, 60 Å, 4 mm)

4.0

1 to 50 ng/mL

[63]

Tacrolimus

Peripheral blood mononuclear cells

Liquideliquid extraction

LC-MS/MS (EIS) positive-ion mode

Xterra C18 (50
2.1 mm; 3.5 mm)

2.0

0.01 to 5.0 ng/mL

[64]

Tacrolimus

Oral fluid

Protein precipitation

LC-MS/MS (EIS) positive-ion mode

Acquity UPLC BEH C18 (50
2.1 mm; 1.7 mm)

2.2

10 to 1600 pg/mL

[65]

Tacrolimus

Bile

Protein precipitation and liquideliquid extraction

LC-MS/MS (EIS) positive-ion mode

C18 Hypersil GOLD (50
2.1 mm; 3 mm)

5.0

0.5 to 20 ng/mL

[66]

Tacrolimus Cyclosporine A

DBS

Liquid extraction

LC-MS/MS (EIS) positive-ion mode

Acquity UPLC BEH C18 (50
2.1 mm; 1.7 mm)

3.0

8.5 to 1500 ng/mL cyclosporine 2.3 to 50 ng/mL tacrolimus

[67]

Everolimus

Peripheral blood mononuclear cells

Protein precipitation

LC-MS/MS (EIS) positive-ion mode

Cartridge MassTrak TDM C18 (2.1
10 mm)

1.5

1.25 to 12.5 ng/mL

[68]

Everolimus Sirolimus

Whole blood

Protein precipitation and online SPE (Cyclone 0.5
50 mm)

LC-MS/MS (APCI) negativeion mode

Hypersil gold C18 (2.1
50 mm; 1.9 mm)

5.8

2.2 to 43.7 ng/mL everolimus 2.9 to 51.2 ng/mL sirolimus

[69]

Cyclosporine A

Hair

Liquideliquid extraction

LC-MS/MS (EIS) positive-ion mode

Acquity UPLC BEH C18 (50
2.1 mm; 1.7 mm)

4.5

100 to 600 pg/mg

[70]

Tacrolimus Cyclosporine A

Whole blood

Protein precipitation

LC-MS/MS (APCI) negativeion mode

C18 SecurityGuard cartridge column (4.0
3.0 mm)

1.5

1.0 to 30 ng/mL tacrolimus 25 to 2000 ng/mL cyclosporine

[71]

Drug class

Sample

Tacrolimus

Cyclosporine A Everolimus Sirolimus Tacrolimus

Whole blood

Semiautomated sample preparation Hamilton STARLet

LC-MS/MS (EIS) positive-ion mode

Hypersil GOLD C18 (20
2.1 mm; 1.9 mm)

2.3

10 to 1500 ng/mL cyclosporine 1.0 to 50 ng/mL everolimus/ sirolimus/tacrolimus

[72]

Cyclosporine A Tacrolimus Everolimus Sirolimus

Whole blood

Commercial Chromsystems immunosuppressant extraction kit

LC-MS/MS (EIS) positive-ion mode

Luna (50
2.1 mm; 5 mm)

3.0

5.0 to 2000 ng/mL cyclosporine A 0.5 to 50 ng/mL everolimus/ sirolimus/tacrolimus

[73]

Cyclosporine A Tacrolimus Everolimus Sirolimus

Whole blood

MEPS

LC-MS/MS (EIS) positive-ion mode

Kinetex C18 column (50
2.1 mm, 2.6 mm)

2.5

3.0 to 1500 ng/mL cyclosporine A 0.5 to 50 ng/mL everolimus/ sirolimus/tacrolimus

[74]

Cyclosporine A Tacrolimus Everolimus Sirolimus Mycophenolic acid

Mycophenolic acid plasma Others: Whole blood

Protein precipitation and online SPE (poros R1/20, 30
2.1 mm, 20 mm)

LC-MS/MS (EIS) positive-ion mode

Phenyl-hexyl C18 XDB (75
3.0 mm, 3.5 mm)

3.5

2.0 to 1250 ng/mL cyclosporine 0.5 to 42.2 ng/mL tacrolimus 0.6 to 49.2 ng/mL sirolimus 0.5 to 40.8 ng/mL everolimus 0.01 to 7.5 ng/mL mycophenolic

[75]

Cyclosporine Tacrolimus Sirolimus Everolimus

Whole blood

Protein precipitation Online SPE (XTerra MS C8, 10
2.1; 5 mm)

LCeMS (EIS) positive-ion mode

XTerra MS C18 (50
2.1; 5 mm)

17.0

50 to 1500 ng/mL Cyclosporine 2,5 to 30 ng/mL others

[76]

Raltegravir Maraviroc Darunavir Etravirine Ritonavir

Plasma

Liquideliquid extraction

LC-MS/MS (EIS) positive-ion mode

Atlantis C18 (50
2.1 mm; 3 mm)

10.0

25 to 10,000 ng/mL darunavir 10 to 4000 ng/mL etravirine 2.5 to 1000 ng/mL Maraviroc 12.5 to 5000 ng/mL raltegravir 5.0 to 2000 ng/mL ritonavir

[77]

Darunavir

Plasma

Liquideliquid extraction

LC-MS/MS (EIS) positive-ion mode

Acquity C18 (50
2.1 mm, 1.7 mm)

15.0

1.0 to 5000 ng/mL

[78]

Efavirenz

Plasma

Protein precipitation

LC-MS/MS (EIS) negative-ion mode

Xbridge C18 (50
2.1 mm, 3.5 mm)

5.0

1.0 to 2500 ng/mL

[79]

Antirretroviral

(Continued)

TABLE 3.1

Overview of mass spectrometric assays for various drug classes.dcont'd Sample preparation technique

Instrumentation

Column

Plasma

SPE (Oasis MCX, 30 mg/1cc)

LC-MS/MS (EIS) positive-ion mode

Chromolith speed rod RP18 (50
4.6 mm)

Tenofovir Lamivudine Nevirapine

Plasma

SPE (MCX, 30 mg/ 1cc)

LC-MS/MS (EIS) negative-ion mode

Indinavir Saquinavir Nelfinavir Amprenavir Darunavir Atazanavir Ritonavir Lopinavir Tipranavir Efavirenz Nevirapine Etravirine Raltegravir

Peripheral blood mononuclear cell

Liquideliquid extraction

Indinavir Saquinavir Nelfinavir Amprenavir Atazanavir Ritonavir Lopinavir Tipranavir Efavirenz Nevirapine

Peripheral blood mononuclear cell

Abacavir Tenofovir Darunavir Raltegravir

Plasma Oral fluid

Drug class

Sample

Emtricitabine Tenofovir

Run time (min)

Analytical range

Reference

2.0

25 to 2500 ng/mL emtricitabine 10 to 600 ng/mL tenofovir

[80]

ProntoSIL C18 AQ (100
4.6 mm; 3 mm)

3.0

2 to 500 ng/mL tenofovir 10 to 4000 ng/mL lamivudine/Nevirapine

[81]

LC-MS (EIS) positive-ion mode, (efavirenz negative mode)

Atlantis T3 C18 (150
2.1 mm, 3 mm)

28.0

1.25 to 320 ng/mL tipranavir 0.125 to 32 ng/mL others

[82]

Liquideliquid extraction

LC-MS/MS (EIS) positive-ion mode

RP-18 (50
2.1 mm)

14.0

0.25 to 125 ng/mL

[83]

Protein precipitation

LC-MS/MS (EIS) positive-ion mode

C18 (50
1.5 mm, 5 mm)

6.0

1.0 5 to 10,000 ng/mL

[84]

Lopinavir Ritonavir

Plasma Semen Oral fluid Plasma ultrafiltrate

Liquideliquid extraction

LC-MS/MS (EIS) positive-ion mode

LiChrocart RP-18 LiChrospher 100 EC (125
4 mm; 5 mm)

4.5

1 to 2000 ng/mL lopinavir 1 to 200 ng/mL ritonavir

[85]

Nevirapine

Hair

Liquideliquid extraction

LC-MS/MS (EIS) positive-ion mode

BDS-C18 (100
4.6 mm)

3.0

0.25 to 100 ng/mg

[86]

Efavirenz Lopinavir Ritonavir

Hair

Liquideliquid extraction

LC-MS/MS (EIS) positive-ion mode, (efavirenz negative mode)

Hypersil-Keystone BDS-C18 (100
4.6 mm) lopinavir/ritonavir BDS-C18 (50
4.6 mm) efavirenz

2.5 efavirenz 5.0 lopinavir/ ritonavir

0.05 to 20 ng/mg efavirenz/ lopinavir 0.01 to 4.0 ng/mg ritonavir

[87]

Darunavir Etravirine

Peripheral blood mononuclear cell

Liquideliquid extraction

LC-MS/MS (EIS) positive-ion mode

C18 (75
2.1 mm; 2.5 mm)

6.5

1.25 to 125 ng/mL

[88]

Lopinavir Ritonavir

DBS Plasma

Liquideliquid extraction

MALDI-QqQ-MS/ MS positive-ion mode

-

<15 s

0.05 to 4.0 mmol/L Plasma 0.25 to 50 mmol/L DBS

[89]

Indinavir Saquinavir Nelfinavir Amprenavir Darunavir Atazanavir Ritonavir Lopinavir Tipranavir Efavirenz Nevirapine Emtricitabine Lamivudine Tenofovir Zidovudine

Serum

Protein precipitation

LC-MS/MS (EIS) positive-ion mode and full scan mode

Hypersil GOLD PFP (100
3 mm; 3 mm)

16.0

1 to 1000 ng/mL

[90]

Amprenavir Atazanavir Boceprevir Darunavir Efavirenz

Plasma

Protein precipitation

LC-MS/MS (EIS) positive-ion mode, (efavirenz negative mode)

Acquity HSS T3 (50
2.1 mm; 1.8 mm)

5.6

19.53 to 5000 ng/mL amprenavir/atazanavir/ boceprevir/elvitegravir 31.25 to 8000 ng/mL darunavir/nevirapine

[91]

(Continued)

TABLE 3.1

Overview of mass spectrometric assays for various drug classes.dcont'd

Drug class Elvitegravir Etravirine Indinavir Lopinavir Maraviroc Nevirapine Raltegravir Ritonavir Saquinavir Tenofovir Tipranavir Lamivudine Stavudine Zidovudine Nevirapine Nelfinavir Ritonavir Lopinavir

Sample

Sample preparation technique

Instrumentation

Column

Run time (min)

Analytical range

Reference

7.81 to 2000 ng/mL etravirine/indinavir/ maraviroc/raltegravir/ ritonavir/saquinavir/ etravirine 78.12 to 20,000 ng/mL lopinavir 6.0 to 500 ng/mL tenofovir 195 to 50,000 ng/mL tipranavir 31.25 to 8000 ng/mL efavirenz 10 to 10,000 ng/mL

[92]

Breast Milk

Protein precipitation, disruption of fat globules and SPE (C18, 1 mL, 100 mg)

LC-MS/MS (EIS) Positive and negative-ion mode

Aquasil C18 (50
2.1 mm; 5 mm)

3.0

Plasma Semen

Protein precipitation

LC-MS/MS (EIS)

Supelcosil C18 ABZ (150
4.6 mm; 3 mm)

8.0

Plasma 15 to 3000 ng/mL zidovudine lamivudine/abacavir 25 to 3000 ng/mL atazanavir/ ritonavir/efavirenz 40 to 8000 ng/mL lopinavir Seminal plasma 20 to 4000 ng/mL zidovudine lamivudine/abacavir Others same as plasma

[93]

Phenytoin

DBS

Liquideliquid extraction

LC-MS/MS (EIS) positive-ion mode

Synergi fusion (50
2 mm; 4 mm)

4.0

0.1 to 100 mg/mL

[94]

Carbamazepine Carbamazepine10,11-epoxide

DBS

Liquideliquid extraction

LC-MS/MS (EIS) positive-ion mode

Synergi fusion (50
2.1 mm; 4 mm)

10.0

1.0 to 40 mg/mL carbamazepine 0.25 to 20 mg/mL carbamazepine-10,11-epoxide

[95]

Abacavir Atazanavir Zidovudine Lamivudine Efavirenz Indinavir Ritonavir Saquinavir Lopinavir Antiepileptic

Phenobarbital

DBS

Liquideliquid extraction

LC-MS/MS (EIS) negative-ion mode

Synergi Fusion-RP 80A (150
2 mm; 4 mm)

<4.0

1.0 to 100 mg/mL

[96]

Valproic acid

DBS

Liquideliquid extraction

GC-MS (EI)

CP-WAX MS (30 m
0.25 mm; 0.25 mm)

8.25

5.0 to 250 mg/mL

[97]

Valproic acid

Plasma

Liquideliquid extraction and derivatization DMF and BSTFA

GC-MS (EI)

HP-5MS (30 m
0.25 mm; 0.25 mm)

10.0

0 to 148.4 mg/mL

[98]

Carbamazepine Carbamazepine10,11-epoxide Phenytoin Valproic acid Gabapentin Lamotrigine Levetiracetam Oxcarbazepine Topiramate Zonisamide

Plasma

Protein precipitation

LC-MS/MS (EIS) positive and negative-ion mode

Luna C18 (100
2.0 mm; 3 mm)

12.0

0.4 to 20 mg/mL carbamazepine 0.2 to 10 mg/mL carb10,11-epoxide 4 to 200 mg/mL phenytoin 10 to 500 mg/mL valproic acid 0.8 to 40 mg/mL gabapentin 0.4 to 20 mg/mL lamotrigine 1.2 to 60 mg/mL levetiracetam 1.2 to 60 mg/mL oxcarbazepine 0.8 to 40 mg/mL topiramate 1.6 to 80 mg/mL zonisamide

[99]

Carbamazepine Carbamazepine10,11-epoxide Clobazam N-desmethylclobazam Clonazepam Diazepam N-desmethyldiazepam, Ethosuximide Felbamate Gabapentin Lamotrigine Levetiracetam

Plasma

Protein precipitation

LC-MS/MS (EIS) short positive and negative-ion mode

Acquity BEH C18 (50
2.1 mm, 1.7 mm)

10.0

1.3 to 13.5 mg/mL carbamazepine 0.9 to 23.8 mg/mL carb10,11-epoxide 0.05 to 0.25 mg/mL clobazam 0.25 to 1.25 mg/mL N-desmethylclobazam 0.01 to 0.05 mg/mL clonazepam 0.1 to 0.5 mg/mL diazepam 0.05 to 0.25 mg/mL N-desmethyldiazepam 20.3 to 254 mg/mL

[100]

(Continued)

TABLE 3.1

Overview of mass spectrometric assays for various drug classes.dcont'd

Drug class

Sample

Sample preparation technique

Instrumentation

Column

Run time (min)

Analytical range

Reference

[101]

[102]

Phenytoin Alprazolam Oxcarbazepine Carbamazepine

Plasma Urine

MEPS (C18 4 mg)

GC-MS (EI)

Rtx-1MS (30 m
0.25 mm; 0.25 mm)

30.33

ethosuximide 4.2 to 105.0 mg/mL felbamate 2.6 to 65.0 mg/mL gabapentin 1.2 to 30.0 mg/mL lamotrigine 1.9 to 48.8 mg/mL levetiracetam 2.0 to 50.0 mg/mL N-desmethylmesuximide 0.02 to 0.1 mg/mL nitrazepam 5.0 to 50.0 mg/mL phenobarbital 2.2 to 53.8 mg/mL phenytoin 1.2 to 28.8 mg/mL primidone 0.6 to 15.0 mg/mL tiagabine 2.1 to 52.5 mg/mL topiramate 10.4 to 260 mg/mL valproic acid 1.1 to 27.5 mg/mL vigabatrin 2.0 to 51.3 mg/mL zonisamide 0.1 to 500.0 ng/mL

Levetiracetam Lamotrigine

Whole blood

SPE (HF bond elut LRC-C18 Derivatization (MTBSTFA TBDMSCl)

GC-MS (EI)

DB-5MS (30 m
0.25 mm; 0.25 mm)

17.0

0.5 to 50.0 mg/mL

N-desmethylmesuximide Nitrazepam Phenobarbital Phenytoin Primidone Tiagabine Topiramate Valproic acid Vigabatrin Zonisamide

Antineoplastic Paclitaxel Docetaxel Vinblastine Vinorelbine

Plasma

Liquideliquid extraction

LC-MS/MS (EIS) positive-ion mode

Zorbax SB-C18 (100
2.1 mm, 3.5 mm)

4.5

25 to 2500 ng/mL Paclitaxel 10 to 1000 ng/mL docetaxel/ vinblastine/vinorelbine

[103]

Irinotecan Irinotecan metabolites

Plasma

Protein precipitation

LC-MS/MS (EIS) positive-ion mode

Gemini C18 (100
2.0 mm; 3 mm)

18.0

10 to 10,000 ng/mL irinotecan 1 to 500 ng/mL for SN-38/SN38 glucuronide 1 to 5000 ng/mL APC

[104]

Methotrexate

Plasma

Protein precipitation

LC-MS/MS (EIS) positive-ion mode

C18 (50
2.1 mm, 3 mm)

5.0

0.05 to 25.0 mM

[105]

Methotrexate polyglutamates (MTXPG15)

Red blood cells

Protein precipitation

LC-MS/MS (EIS) positive-ion mode

Acquity BEH C18 (100
2.1 mm, 1.7 mm)

6.0

0.97 to 1000 nM

[106]

5-Fluorouracil Tegafur Gimeracil Potassium oxonate

Plasma

Protein precipitation (plus derivatization for oxonate

LC-MS/MS (EIS) negative-ion mode (APCI) positiveion mode for oxonate

Synergi Hydro-RP (150
4.6 mm, 4 mm) Zorbax SB-C18 (150
4.6 mm, 5 mm) for oxonate

8.0

2.0 to 500 ng/mL 5-fluorouracil 2.0 to 500 ng/mL tegafur 12 to 3000 ng/mL gimeracil 2.0 to 150 ng/mL potassium oxonate

[107]

5-Fluorouracil 5-Fluorouracil metabolite Uracil Uracil metabolite

Plasma

Liquideliquid extraction

LC-MS/MS (EIS) positive-ion mode

Atlantis dC18 (150
2.0 mm; 3 mm)

10.0

0.01 to 10 mM uracil 0.1 to 10 mM dihydrouracil 0.1 to 75 mM 5-fluorouracil 0.75 to 75 mM for dihydrofluorouracil

[108]

Oxaliplatin

Plasma ultrafiltrate

Protein precipitation

LC-MS/MS (EIS) positive-ion mode

Beckman RP18 (250
4.6 mm, 5 mm)

10.0

20 to 1000 ng/mL

[109]

Cyclophosphamide

Plasma

MEPS (100 mL syringe, C2-sorbent)

LC-MS/MS (EIS) positive-ion mode

Zorbax SB-C18 (50
2.1 mm, 3.5 mm)

12.5

0.5 to 150 mg/mL

[110]

Vincristine

Plasma

SPE (Oasis HLB 1ml/10 mg)

LC-MS/MS (EIS) positive-ion mode

Luna C8 (50
2.0 mm; 3 mm)

8.0

0.25 to 50 ng/mL

[111] (Continued)

TABLE 3.1

Overview of mass spectrometric assays for various drug classes.dcont'd

Drug class

Sample

Sample preparation technique

Imatinib Nilotinib Dasatinib Sunitinib Sorafenib Lapatinib

Plasma

Imatinib Imatinib metabolite Nilotinib Lapatinib Erlotinib Sorafenib Dasatinib Axitinib

Instrumentation

Column

Protein precipitation

LC-MS/MS (EIS) positive-ion mode

XTerra dC18 (50
2.1 mm, 5 mm)

Plasma

SPE (Oasis MCX mElution 96-well)

LC-MS/MS (EIS) positive-ion mode

Imatinib

DBS

Liquideliquid extraction

Imatinib

Hair

Paclitaxel

Run time (min)

Analytical range

Reference

20.0

1.0 to 10,000 ng/mL imatinib 1.0 to 5000 ng/mL nilotinib 1.0 to 4000 ng/mL dasatinib 1.0 to 4000 ng/mL sunitinib 100 to 15,000 ng/mL sorafenib 5 to 5000 ng/mL lapatinib

[112]

Acquity C18 BEH (50
2.1 mm,1.7 mm)

4.0

10 to 5000 ng/mL imatinib and metabolite/nilotinib/ lapatinib/erlotinib/sorafenib 0.1 to 200 ng/mL dasatinib/ axitinib/gefitinib/sunitinib

[113]

LC-MS/MS (EIS) positive-ion mode

Kinetex C18 (50
4.6 mm, 2.6 mm)

10.0

50 to 4000 ng/mL

[114]

Liquideliquid extraction

LC-MS/MS (EIS) positive-ion mode

XTerra C8 (50
2.1 mm, 3.5 mm)

6.5

0.5 to 25 ng/mg

[115]

DBS

Liquideliquid extraction

LC-MS/MS (EIS) positive-ion mode

Kinetex C18 (50
4.6 mm, 2.6 mm)

2.3

2.5 to 400 ng/mL

[116]

Tamoxifen Tamoxifen metabolites

DBS

Liquideliquid extraction

LC-MS/MS (EIS) positive-ion mode

Acquity C18 BEH (150
2.1 mm,1.7 mm)

8.0

7.5 to 300 ng/mL tamoxifen 15 to 600 ng/mL N-desmethyltamoxifen 1.0 to 40 ng/mL endoxifen 0.5 to 50 ng/mL hydroxytamoxifen

[117]

Busulfan

DBS

Liquideliquid extraction

LC-MS/MS (EIS) positive-ion mode

Kinetex C18 (50
4.6 mm, 2.6 mm)

7.0

100 to 200 ng/mL

[118]

Psychotropics Amitriptyline Nortriptyline Citalopram Clomipramine Fluvoxamine Imipramine Fluoxetine Paroxetine Sertraline Venlafaxine

Plasma Oral fluid

Automated SPE (OASIS MCX, 3 cm3 60 mg)

LC-MS/MS (EIS) positive-ion mode

Sunfire C18 (20
2.1 mm, 3.5 mm)

5.0

2 to 500 ng/mL oral fluid 10 to 1000 ng/mL plasma fluvoxamine/clomipramine 4 to 1000 ng/mL plasma amitriptyline/nortriptyline 2 to 1000 ng/mL plasma others

[119]

Amitriptyline Desipramine Imipramine Nortriptyline

Serum

Protein precipitation

LC-MS/MS (EIS) positive-ion mode

Hypersil GOLD C18 (50
2.1 mm, 3 mm)

3.5

10 to 1000 ng/mL amitriptyline 14 to 1000 ng/mL desipramine 19 to 1000 ng/mL imipramine 21 to 1000 ng/mL nortriptyline

[120]

Amitriptyline Clomipramine Desmethylclomipramine Imipramine Nortriptyline

DBS

Liquideliquid extraction

LC-MS/MS (EIS) positive-ion mode

HyPURITY Aquastar (50
2.1 mm, 5 mm)

4.8

20 to 500 ng/mL

[121]

Amitriptyline Citalopram Clomipramine Desipramine Dosulepin Doxepin Duloxetine Fluoxetine Fluvoxamine Imipramine

Plasma

Liquideliquid extraction

LC-MS/MS (EIS) positive-ion mode

Acquity C18 BEH (100
2.1 mm,1.7 mm)

10.0

2.5 to 250 ng/mL paroxetine/ citalopram/duloxetine/ mianserin/mirtazapine 10 to 1000 ng/mL others

[122]

(Continued)

TABLE 3.1

Overview of mass spectrometric assays for various drug classes.dcont'd

Drug class

Sample

Sample preparation technique

Instrumentation

Column

Maprotiline Mianserin Mirtazapine Moclobemide Nortriptyline Paroxetine Reboxetine Sertraline Trazodone Venlafaxine Metabolites Citalopram Desmethylcitalopram

Plasma Breast milk

Protein precipitation SPE (Oasis MCX)

LC-MS/MS (EIS) positive-ion mode

Enantioselective separation Lux Cellulose-2 (4.6
150 mm; 5 mm)

Fluoxetine Mirtazapine Norfluoxetine Paroxetine Sertraline Olanzapine Venlafaxine

Plasma

Liquideliquid extraction (fluoxetine, norfluoxetine, sertraline, paroxetine, derivatization HFBI)

GC-MS (EI)

Fluoxetine

Plasma

Protein precipitation Derivatization SBSE Thermal desorption

TSD-GC-MS (EI)

Run time (min)

Analytical range

Reference

27.5

0.1 to 100 ng/mL S-(þ)/R-() citalopram 0.3 to 100 ng/mL S-(þ)/R()-desmethylcitalopram

[123]

HP5 MS (30 m
0.25 mm; 0.5ìm)

27.8

100 to 2000 ng/mL fluoxetine/norfluoxetine/ venlafaxine 20 to 1000 ng/mL mirtazapine 10 to 1000 ng/mL sertraline 5.0 to 400 ng/mL paroxetine 30 to 1000 ng/mL olanzapine

[124]

HP5 MS (30 m
0.25 mm; 0.25 mm)

12.5

1.0 to 500 ng/mL

[125]

Chlorpromazine Haloperidol Cyamemazine Quetiapine Clozapine Olanzapine Levomepromazine

Plasma

MEPS Derivatization MSTFA with 5% TMS

GC-MS/MS Positive electron ionization mode

HP5 MS (30 m
0.25 mm; 0.25 mm)

25.0

1.0 to 1000 ng/mL chlorpromazine/clozapine 6.0 to 200 ng/mL haloperidol 4.0 to 1000 ng/mL cyamemazine/quetiapine/ levomepromazine 0.8 to 200 ng/mL olanzapine

[126]

Amisulpride Aripiprazole Clozapine Olanzapine Quetiapine Risperidone Sulpiride Metabolites

Human plasma Serum Oral fluid Hemolyzed whole blood

Liquideliquid extraction

LC-MS/MS (APCI) positiveion mode

Spherisorb S5SCX sulfopropylmodified silica (100
2.1 mm; 5 mm)

6.5

10 to 500 ng/mL amisulpride aripiprazole/ dehydroaripiprazole 10 to 2000 ng/mL clozapine/ norclozapine 2.0 to 200 ng/mL olanzapine/ risperidone/ 9-hydroxyrisperidone 10 to 800 ng/mL quetiapine/ sulpiride

[127]

Amisulpride Aripiprazole Asenapine Bromperidol Clozapine Haloperidol Iloperidone Levosulpiride Lurasidone Olanzapine Paliperidone Pipamperone Quetiapine Risperidone Sertindole Zuclopenthixol Metabolites

DBS

Liquideliquid extraction

LC-MS/MS (EIS) positive-ion mode

SB C18 (50
2.1 mm; 1.7 mm)

6.0

0.5 to 50 ng/mL haloperidol/ iloperidone 1.0 to 100 ng/mL asenapine/ bromperidol/quetiapine 1.0 to 150 ng/mL risperidone 1.0 to 300 ng/mL zuclopenthixol/paliperidone/ olanzapine 5.0 to 400 ng/mL sertindole 5.0 to 1000 ng/mL lurasidone 10 to 1200 ng/mL amisulpride 10 to 1500 ng/mL quetiapine 20 to 1500 ng/mL aripiprazole/50 to 1500 ng/ mL clozapine/levosulpiride

[128]

(Continued)

TABLE 3.1

Overview of mass spectrometric assays for various drug classes.dcont'd

Drug class

Sample

Amitriptyline Clomipramine Clozapine Norclozapine Quetiapine Duloxetine Imipramine Fluoxetine Norfluoxetine Citalopram Paroxetine Sertraline Norsertraline Venlafaxine Promethazine Alprazolam Clonazepam Diazepam Nordiazepam Lorazepam Lormetazepam Medazepam Oxazepam

Neonatal meconium Maternal hair

Sample preparation technique

Instrumentation

Column

Liquideliquid extraction

LC-MS/MS (EIS) positive-ion mode

Acquity UPLC HSS C18 (150
2.1 mm; 1.8 mm)

Run time (min) 15.0

Analytical range

Reference

0.05e1 to 10 ng/mg hair 5e25 to 1000 ng/g meconium

[129]

APCI, atmospheric-pressure chemical ionization; DBS, dried blood spot; EI, electron impact; EIS, electrospray ion source; LC-MS, liquid chromatographyemass spectrometry; LC-MS/MS, liquid chromatography tandem mass spectrometry; MEPS, microextraction in packed sorbent; GC-MS, gas chromatographyemass spectrometry; SBSE, stir bar sorptive extraction; SPE, solid-phase extraction; TDS, thermal desorption system; VAMS, volumetric absorptive microsampling device.

References

71

3.5 Conclusions Mass spectrometry allows sensitive and specific determination of drugs and metabolites in a range of biological specimens, both classic such as plasma and alternative such as DBS. The use of mass spectrometric assays in the field of TDM requires extensive validation with a special focus on matrix effects, which can have a major impact on the performance of the assays. There are numerous reports on the use of mass spectrometry coupled to both gas and liquid chromatography for many important classes of drugs of relevance for TDM. Particularly, LC-MS/MS is currently the mainstay of comprehensive drug measurement in biosamples, being a fundamental resource for laboratories working in the field of TDM.

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