Abstract
Utilizing tigecycline-d9 as an internal standard (IS), we establish and validate a simple, effective, and rapid liquid chromatography-tandem mass spectrometry (LC-MS/MS) method for the quantitative measurement of tigecycline (TGC) in patient plasma. Acetonitrile was used as a precipitant to process plasma samples by a protein precipitation method. The analyte and IS were separated on an HSS T3 (2.1 × 100 mm, 3.5 μm) chromatographic column using isocratic program with a mobile phase comprising of 80% solvent A (water containing 0.1% formic acid (v/v) with 5 mM ammonium acetate) and 20% solvent B (acetonitrile) with a flow rate of 0.3 mL/min. The mass spectrometer, scanning in multireaction monitoring (MRM) mode and using an electrospray ion source (ESI), operated in the positive-ion mode. The ion pairs used for quantitative analysis were m/z 586.4 ⟶ 513.3 and m/z 595.5 ⟶ 514.3 for TGC and the IS, respectively. The range of the linear calibration curve obtained with this approach was 50–5000 ng/ml. Intra- and interbatch precision for TGC quantitation were less than 7.2%, and the accuracy ranged from 93.4 to 101.8%. The IS-normalized matrix effect was 87 to 104%. Due to its high precision and accuracy, this novel method allows for fast quantitation of TGC with a total analysis time of 2 min. This approach was effectively applied to study the pharmacokinetics of TGC in critically ill adult patients.
Highlights
Tigecycline (TGC) is the first member of the glycylcycline class of antimicrobial agents and is associated with refractory infections in critically ill patients [1, 2]. ough high-dose tigecycline (200 mg loading dose, 100 mg q12 h) were recommended for the treatment of severe infections [3,4,5], a black box warning of increased all-cause mortality was issued by the Food and Drug Administration (FDA) [6]. e area under the concentration-time curve from 0 to 24 h at stead -state (AUC24) divided by the minimal inhibitory concentration (MIC) is often used as the pharmacokinetic/ pharmacodynamic (PK/PD) index, with target values calculated for various infections [7,8,9,10,11]
E current research established a sensitive, simple, and rapid LC-MS/MS method for the quantitative analysis of TGC in patient plasma, utilizing tigecycline-d9 (TGC-d9) as an internal standard (IS). e influence of abnormal plasma on the matrix effect of TGC was investigated in the full method validation. is approach was applied to analyze 222 samples collected from 74 ICU patients for a population pharmacokinetic (PPK) study
Mass Spectrometric Conditions. e mass spectrometer, scanning in multireaction monitoring (MRM) mode and using an electrospray ion source (ESI), operated in positive ion mode. e ion pairs used for quantitative analysis were m/z 586.4 ⟶ 513.3 for TGC (Figure 1(a)) and m/z 595.5 ⟶ 514.3 for the IS (Figure 1(b)). e positive electrospray ionization source (ESI+) temperature was 550°C; the ion spray voltage was 4500 V; and the declustering potential, entrance potential, and collision energies were 52 eV, 10 eV, and 20 eV for TGC and 70 eV, 10 eV, and 42 eV for the IS, respectively
Summary
Tigecycline (TGC) is the first member of the glycylcycline class of antimicrobial agents and is associated with refractory infections in critically ill patients [1, 2]. ough high-dose tigecycline (200 mg loading dose, 100 mg q12 h) were recommended for the treatment of severe infections [3,4,5], a black box warning of increased all-cause mortality was issued by the Food and Drug Administration (FDA) [6]. e area under the concentration-time curve from 0 to 24 h at stead -state (AUC24) divided by the minimal inhibitory concentration (MIC) is often used as the pharmacokinetic/ pharmacodynamic (PK/PD) index, with target values calculated for various infections [7,8,9,10,11]. Tigecycline (TGC) is the first member of the glycylcycline class of antimicrobial agents and is associated with refractory infections in critically ill patients [1, 2]. International Journal of Analytical Chemistry frequently occurs in critically ill patients [14,15,16,17,18]. Hemolysis may occur during blood collection and processing, and hyperlipidemic samples are not rare in clinical sampling, especially in critically ill patients. The matrix effect of TGC in such abnormal plasma has not yet been reported. E current research established a sensitive, simple, and rapid LC-MS/MS method for the quantitative analysis of TGC in patient plasma, utilizing tigecycline-d9 (TGC-d9) as an internal standard (IS). E influence of abnormal plasma on the matrix effect of TGC was investigated in the full method validation. E current research established a sensitive, simple, and rapid LC-MS/MS method for the quantitative analysis of TGC in patient plasma, utilizing tigecycline-d9 (TGC-d9) as an internal standard (IS). e influence of abnormal plasma on the matrix effect of TGC was investigated in the full method validation. is approach was applied to analyze 222 samples collected from 74 ICU patients for a population pharmacokinetic (PPK) study
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