Determination of Pharmacokinetic Parameters by HPLC‐MS/MS and UPLC‐MS/MS

Þorsteinsdóttir, Margrét; Sigurdsson, Baldur B.; Bragason, Gísli

doi:10.1002/9781118180730.ch8

Cited by 2 publications

(13 citation statements)

References 23 publications

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“…Optimization of the UPLC–MS/MS quantification method was carried out using a chemometric approach [22–25]. The assay was pre-validated in terms of selectivity, sensitivity, concentration function, accuracy, precision, carryover, stability and matrix effect for diluted urine samples [26,27].…”

Section: Introductionmentioning

confidence: 99%

Quantitative UPLC–MS/MS assay of urinary 2,8-dihydroxyadenine for diagnosis and management of adenine phosphoribosyltransferase deficiency

Þorsteinsdóttir

Eiríksson

et al. 2016

Journal of Chromatography B

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Adenine phosphoribosyltransferase (APRT) deficiency is a hereditary disorder that leads to excessive urinary excretion of 2,8-dihydroxyadenine (DHA), causing nephrolithiasis and chronic kidney disease. Treatment with allopurinol or febuxostat reduces DHA production and attenuates the renal manifestations. Assessment of DHA crystalluria by urine microscopy is used for therapeutic monitoring, but lacks sensitivity. We report a high-throughput assay based on ultra-performance liquid chromatography coupled to tandem mass spectrometry (UPLC–MS/MS) for quantification of urinary DHA. The UPLC–MS/MS assay was optimized by a chemometric approach for absolute quantification of DHA, utilizing isotopically labeled DHA as an internal standard. Experimental screening was conducted with D-optimal design and optimization of the DHA response was performed with central composite face design and related to the peak area of DHA using partial least square regression. Acceptable precision and accuracy of the DHA concentration were obtained over a calibration range of 100 to 5000 ng/mL on three different days. The intra- and inter-day accuracy and precision coefficients of variation were well within ±15% for quality control samples analyzed in replicates of six at three concentration levels. Absolute quantification of DHA in urine samples from patients with APRT deficiency was achieved wihtin 6.5 min. Measurement of DHA in 24 h urine samples from three patients with APRT deficiency, diluted 1:15 (v/v) with 10 mM ammonium hydroxide (NH4OH), yielded a concentration of 3021, 5860 and 10563 ng/mL and 24 h excretion of 816, 1327 and 1649 mg, respectively. A rapid and robust UPLC–MS/MS assay for absolute quantification of DHA in urine was successfully developed. We believe this method will greatly facilitate diagnosis and management of patients with APRT deficiency.

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Section: Introductionmentioning

confidence: 99%

Quantitative UPLC–MS/MS assay of urinary 2,8-dihydroxyadenine for diagnosis and management of adenine phosphoribosyltransferase deficiency

Þorsteinsdóttir

Eiríksson

et al. 2016

Journal of Chromatography B

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“…Flow rate was set at 0.3 ml/min, steepness of gradient was 2 min., initial amount of organic solvent was 15%, type of gradient slope was 4, capillary voltage was 2 kV, cone voltage was 50 V, ion energy was 1.5 V and hexapole 2 was 0.3 V. (H) Response surface plot of retention time (left) and peak area (right) from the optimizations study with the UPLC‐MS/MS method as a function of collision energy and cone voltage, at pH 5.6 and gradient steepness 2 min. Adapted from the study of Thorsteinsdottir et al 34 …”

Section: Design Of Experimentsmentioning

confidence: 99%

“…The analysis of DoE experimental data consists of three primary stages (Figure 3A-H, the data is adapted from a study of Thorsteinsdottir et al 34 ):…”

Section: Step 6: Data Analysis and Interpretationmentioning

confidence: 99%

“…The initial amount of organic phase in the mobile phase had a negative significant effect on both responses, the steepness of the gradient had a negative effect on peak area but a positive significant effect on retention time, the injection volume had a positive significant effect on peak area but did not influence the retention time and flow rate had a negative significant effect on both responses. The pH of the mobile phase did not influence the retention time, but much higher peak This case study is adapted with permission from Thorsteinsdottir et al 34 with the goal to optimize a LC-MS/MS method for support of PK evaluation of a drug candidate and two metabolites in plasma. A validated HPLC-MS/MS assay was utilized for PK evaluation during pre-clinical studies; however, the method lacked sufficient sensitivity for support of PK evaluation during clinical studies.…”

Section: Doe Analysis and Interpretationmentioning

confidence: 99%

“…The second case demonstrates the importance of selection of factors and factor ranges depending on the analytical platform used for optimization of a quantification method. 34 The third case demonstrates the capabilities of DoE for optimization of both quantitative factors and multilevel qualitative factors by D-optimal design for the development and optimization of a UPLC-MS/MS method for quantification of biomarkers in urine for support of clinical diagnosis and therapeutic drug monitoring of patients with adenine phosphoribosyltransferase (APRT) deficiency. 19…”

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Design of experiments for development and optimization of a liquid chromatography coupled to tandem mass spectrometry bioanalytical assay

Þorsteinsdóttir

2021

J Mass Spectrom

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Design of experiments (DoE) is a valuable tool for the optimization of quantitative bioanalytical methods utilizing liquid chromatography coupled to tandem mass spectrometry (LC–MS/MS). Liquid chromatography mass spectrometry (LC–MS) is composed of several processes, including, liquid introduction and analyte ionization. The goal is to transfer analytes from atmospheric pressure to vacuum and maintain conditions that are compatible for both LC and MS. These processes involve many experimental factors which need to be simultaneously optimized to obtain maximum sensitivity and resolution at minimum retention time. In this tutorial, the basic concepts of DoE will be explained with focus on practical use of DoE. Three case studies optimized with DoE for liquid chromatography tandem mass spectrometry (LC–MS/MS) quantitative assays will then be presented.

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Determination of Pharmacokinetic Parameters by HPLC‐MS/MS and UPLC‐MS/MS

Cited by 2 publications

References 23 publications

Quantitative UPLC–MS/MS assay of urinary 2,8-dihydroxyadenine for diagnosis and management of adenine phosphoribosyltransferase deficiency

Quantitative UPLC–MS/MS assay of urinary 2,8-dihydroxyadenine for diagnosis and management of adenine phosphoribosyltransferase deficiency

Design of experiments for development and optimization of a liquid chromatography coupled to tandem mass spectrometry bioanalytical assay

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