Method development for quantitative determination of seven statins including four active metabolites by means of high-resolution tandem mass spectrometry applicable for adherence testing and therapeutic drug monitoring
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Lea Wagmann
Abstract
Background
Statins are used to treat and prevent cardiovascular diseases (CVDs) by reducing the total serum cholesterol concentration. Unfortunately, dose-related side effects and sub-optimal response, attributed to non-adherence amongst others, were described. Therefore, a fast and sensitive liquid chromatography-high-resolution tandem mass spectrometry (LC-HRMS/MS) method for adherence testing and therapeutic drug monitoring of all currently marketed statins and their active metabolites in human blood plasma should be developed, validated and tested for applicability.
Methods
Atorvastatin, fluvastatin, lovastatin, pitavastatin, pravastatin, rosuvastatin, and simvastatin, as well as ortho- and para-hydroxy-atorvastatin, lovastatin hydroxy acid and simvastatin hydroxy acid were included and several internal standards (IS) tested. Validation was performed according to the guideline of the European Medicines Agency including selectivity, carry-over, accuracy, precision, matrix effects, dilution integrity and analyte stability. Finally, applicability was tested using 14 patient samples submitted for regular toxicological analysis.
Results
Due to an analytical interference of atorvastatin-d5, diazepam-d5 and pentobarbital-d5 were chosen as IS for positive and negative ionization mode, respectively. All statins and metabolites fulfilled the validation acceptance criteria except for fluvastatin, which could not be quantified reliably and reproducibly, most probably due to instability. Analyses of human plasma samples revealed concentrations of statins and metabolites below the reference plasma concentrations in the case of eight patients. However, nothing was known concerning patients’ adherence and time between intake and sampling.
Conclusions
An LC-HRMS/MS method for identification and quantification of atorvastatin, lovastatin, pitavastatin, pravastatin, rosuvastatin, simvastatin and four active metabolites was successfully developed and applicability demonstrated.
Acknowledgments
The authors like to thank Thomas P. Bambauer and Armin A. Weber for their support.
Author contributions: All the authors have accepted responsibility for the entire content of this submitted manuscript and approved submission.
Financial support: None declared.
Employment or leadership: None declared.
Honorarium: None declared.
Competing interests: The funding organization(s) played no role in the study design; in the collection, analysis, and interpretation of data; in the writing of the report; or in the decision to submit the report for publication.
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©2020 Walter de Gruyter GmbH, Berlin/Boston
Articles in the same Issue
- Frontmatter
- Editorial
- Advancements in mass spectrometry as a tool for clinical analysis: Part I
- Drug adherence, testing and therapeutic monitoring
- Hyphenated mass spectrometry techniques for assessing medication adherence: advantages, challenges, clinical applications and future perspectives
- Method development for quantitative determination of seven statins including four active metabolites by means of high-resolution tandem mass spectrometry applicable for adherence testing and therapeutic drug monitoring
- Validation of a liquid chromatography tandem mass spectrometry (LC-MS/MS) method to detect cannabinoids in whole blood and breath
- THC and CBD concentrations in blood, oral fluid and urine following a single and repeated administration of “light cannabis”
- Identification of metabolites of peptide-derived drugs using an isotope-labeled reporter ion screening strategy
- Validation according to European and American regulatory agencies guidelines of an LC-MS/MS method for the quantification of free and total ropivacaine in human plasma
- Enhanced specificity due to method specific limits for relative ion intensities in a high-performance liquid chromatography – tandem mass spectrometry method for iohexol in human serum
- Small molecule biomarkers
- Applying mass spectrometry-based assays to explore gut microbial metabolism and associations with disease
- Trimethylamine-N-oxide (TMAO) determined by LC-MS/MS: distribution and correlates in the population-based PopGen cohort
- Development of a total serum testosterone, androstenedione, 17-hydroxyprogesterone, 11β-hydroxyandrostenedione and 11-ketotestosterone LC-MS/MS assay and its application to evaluate pre-analytical sample stability
- Short-term stability of free metanephrines in plasma and whole blood
- Validation of a rapid, comprehensive and clinically relevant amino acid profile by underivatised liquid chromatography tandem mass spectrometry
- UPLC-MS/MS method for determination of retinol and α-tocopherol in serum using a simple sample pretreatment and UniSpray as ionization technique to reduce matrix effects
- Independent association of plasma xanthine oxidoreductase activity with serum uric acid level based on stable isotope-labeled xanthine and liquid chromatography/triple quadrupole mass spectrometry: MedCity21 health examination registry
- Serum bile acids profiling by liquid chromatography-tandem mass spectrometry (LC-MS/MS) and its application on pediatric liver and intestinal diseases
- LC-MS/MS analysis of plasma glucosylsphingosine as a biomarker for diagnosis and follow-up monitoring in Gaucher disease in the Spanish population
- Dried blood spots and alternative sample mediums
- Investigating the suitability of high-resolution mass spectrometry for newborn screening: identification of hemoglobinopathies and β-thalassemias in dried blood spots
- Candidate reference method for determination of vitamin D from dried blood spot samples
- Therapeutic drug monitoring of anti-epileptic drugs – a clinical verification of volumetric absorptive micro sampling
- Simultaneous quantitation of five triazole anti-fungal agents by paper spray-mass spectrometry
- Obtaining information from the brain in a non-invasive way: determination of iron in nasal exudate to differentiate hemorrhagic and ischemic strokes
Articles in the same Issue
- Frontmatter
- Editorial
- Advancements in mass spectrometry as a tool for clinical analysis: Part I
- Drug adherence, testing and therapeutic monitoring
- Hyphenated mass spectrometry techniques for assessing medication adherence: advantages, challenges, clinical applications and future perspectives
- Method development for quantitative determination of seven statins including four active metabolites by means of high-resolution tandem mass spectrometry applicable for adherence testing and therapeutic drug monitoring
- Validation of a liquid chromatography tandem mass spectrometry (LC-MS/MS) method to detect cannabinoids in whole blood and breath
- THC and CBD concentrations in blood, oral fluid and urine following a single and repeated administration of “light cannabis”
- Identification of metabolites of peptide-derived drugs using an isotope-labeled reporter ion screening strategy
- Validation according to European and American regulatory agencies guidelines of an LC-MS/MS method for the quantification of free and total ropivacaine in human plasma
- Enhanced specificity due to method specific limits for relative ion intensities in a high-performance liquid chromatography – tandem mass spectrometry method for iohexol in human serum
- Small molecule biomarkers
- Applying mass spectrometry-based assays to explore gut microbial metabolism and associations with disease
- Trimethylamine-N-oxide (TMAO) determined by LC-MS/MS: distribution and correlates in the population-based PopGen cohort
- Development of a total serum testosterone, androstenedione, 17-hydroxyprogesterone, 11β-hydroxyandrostenedione and 11-ketotestosterone LC-MS/MS assay and its application to evaluate pre-analytical sample stability
- Short-term stability of free metanephrines in plasma and whole blood
- Validation of a rapid, comprehensive and clinically relevant amino acid profile by underivatised liquid chromatography tandem mass spectrometry
- UPLC-MS/MS method for determination of retinol and α-tocopherol in serum using a simple sample pretreatment and UniSpray as ionization technique to reduce matrix effects
- Independent association of plasma xanthine oxidoreductase activity with serum uric acid level based on stable isotope-labeled xanthine and liquid chromatography/triple quadrupole mass spectrometry: MedCity21 health examination registry
- Serum bile acids profiling by liquid chromatography-tandem mass spectrometry (LC-MS/MS) and its application on pediatric liver and intestinal diseases
- LC-MS/MS analysis of plasma glucosylsphingosine as a biomarker for diagnosis and follow-up monitoring in Gaucher disease in the Spanish population
- Dried blood spots and alternative sample mediums
- Investigating the suitability of high-resolution mass spectrometry for newborn screening: identification of hemoglobinopathies and β-thalassemias in dried blood spots
- Candidate reference method for determination of vitamin D from dried blood spot samples
- Therapeutic drug monitoring of anti-epileptic drugs – a clinical verification of volumetric absorptive micro sampling
- Simultaneous quantitation of five triazole anti-fungal agents by paper spray-mass spectrometry
- Obtaining information from the brain in a non-invasive way: determination of iron in nasal exudate to differentiate hemorrhagic and ischemic strokes
