Quantitation of the anticancer drug abiraterone and its metabolite Δ(4)-abiraterone in human plasma using high-resolution mass spectrometry

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Abstract

Abiraterone acetate is administered as a prodrug to patients with metastatic, castration-resistant prostate cancer (mCRPC) and is readily metabolized into the potent 17a-hydroxylase/17,20-lyase (CYP17) enzyme inhibitor and androgen receptor inhibitor abiraterone and Δ(4)-abiraterone (D4A), respectively. To investigate pharmacokinetic variability in abiraterone acetate metabolism we developed highly sensitive liquid chromatography/mass spectrometry (LC/MS) assays for the simultaneous quantitation of abiraterone and D4A in human plasma using high-resolution mass spectrometry (HRMS) on an Orbitrap mass spectrometer. This study demonstrates the quantitative performance of HRMS and compares the conventional Parallel Reaction Monitoring (PRM) mode of quantitation with the unconventional Full scan MS mode conducted at high resolution ( > 70,000 resolution). The use of HRMS for quantitation of abiraterone and D4A yielded assays that were linear over a broad concentration range (0.074–509.6 ng/mL for abiraterone; 0.075–59.93 ng/mL for D4A) in both Full scan MS and PRM modes. The assay precision for abiraterone and D4A was below 5% in PRM mode and 7% in Full scan MS mode. Accuracies fell within 98–107% for abiraterone and 104–112% for D4A in PRM mode, and 96–116% for abiraterone and 96–105% for D4A in Full scan MS mode, each meeting the acceptance criteria of FDA approved guidelines for bioanalytical methods The PRM analysis of abiraterone and D4A provided high specificity and reduced background interference, however the Full scan MS detection at a resolution of 70,000 was advantageous in that it required minimal optimization, was simple to implement, yielded comparable quantitative characteristics to PRM and the data is useful for re-analysis. Use of the assays were demonstrated for quantitation of these metabolites in steady state trough level plasma of seventeen (17) patients with mCRPC, demonstrating the inter-patient variability of up to 10-fold concentration.
LanguageEnglish
Pages66-74
Number of pages9
JournalJournal of Pharmaceutical and Biomedical Analysis
Volume154
DOIs
Publication statusPublished - 30 May 2018

Fingerprint

Plasma (human)
Metabolites
Mass spectrometry
Mass Spectrometry
Pharmaceutical Preparations
Monitoring
Assays
Steroid 17-alpha-Hydroxylase
Castration
Prostatic Neoplasms
abiraterone
Pharmacokinetics
Liquid chromatography
Prodrugs
Androgen Receptors
Enzyme Inhibitors
Mass spectrometers
Mixed Function Oxygenases
Metabolism
Liquid Chromatography

Keywords

  • abiraterone
  • high-resolution mass spectrometry
  • metabolomics
  • pharmacokinetics
  • prostate cancer

Cite this

@article{f4d89fae3bee430e9ee8bf0d96fa19fd,
title = "Quantitation of the anticancer drug abiraterone and its metabolite Δ(4)-abiraterone in human plasma using high-resolution mass spectrometry",
abstract = "Abiraterone acetate is administered as a prodrug to patients with metastatic, castration-resistant prostate cancer (mCRPC) and is readily metabolized into the potent 17a-hydroxylase/17,20-lyase (CYP17) enzyme inhibitor and androgen receptor inhibitor abiraterone and Δ(4)-abiraterone (D4A), respectively. To investigate pharmacokinetic variability in abiraterone acetate metabolism we developed highly sensitive liquid chromatography/mass spectrometry (LC/MS) assays for the simultaneous quantitation of abiraterone and D4A in human plasma using high-resolution mass spectrometry (HRMS) on an Orbitrap mass spectrometer. This study demonstrates the quantitative performance of HRMS and compares the conventional Parallel Reaction Monitoring (PRM) mode of quantitation with the unconventional Full scan MS mode conducted at high resolution ( > 70,000 resolution). The use of HRMS for quantitation of abiraterone and D4A yielded assays that were linear over a broad concentration range (0.074–509.6 ng/mL for abiraterone; 0.075–59.93 ng/mL for D4A) in both Full scan MS and PRM modes. The assay precision for abiraterone and D4A was below 5{\%} in PRM mode and 7{\%} in Full scan MS mode. Accuracies fell within 98–107{\%} for abiraterone and 104–112{\%} for D4A in PRM mode, and 96–116{\%} for abiraterone and 96–105{\%} for D4A in Full scan MS mode, each meeting the acceptance criteria of FDA approved guidelines for bioanalytical methods The PRM analysis of abiraterone and D4A provided high specificity and reduced background interference, however the Full scan MS detection at a resolution of 70,000 was advantageous in that it required minimal optimization, was simple to implement, yielded comparable quantitative characteristics to PRM and the data is useful for re-analysis. Use of the assays were demonstrated for quantitation of these metabolites in steady state trough level plasma of seventeen (17) patients with mCRPC, demonstrating the inter-patient variability of up to 10-fold concentration.",
keywords = "abiraterone, high-resolution mass spectrometry, metabolomics, pharmacokinetics, prostate cancer",
author = "Atul Bhatnagar and McKay, {Matthew J.} and McKay, {Matthew J.} and Megan Crumbaker and Ketan Ahire and Peter Karuso and Howard Gurney and Molloy, {Mark P.}",
year = "2018",
month = "5",
day = "30",
doi = "10.1016/j.jpba.2018.03.012",
language = "English",
volume = "154",
pages = "66--74",
journal = "Journal of Pharmaceutical and Biomedical Analysis",
issn = "0731-7085",
publisher = "Elsevier",

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TY - JOUR

T1 - Quantitation of the anticancer drug abiraterone and its metabolite Δ(4)-abiraterone in human plasma using high-resolution mass spectrometry

AU - Bhatnagar,Atul

AU - McKay,Matthew J.

AU - McKay,Matthew J.

AU - Crumbaker,Megan

AU - Ahire,Ketan

AU - Karuso,Peter

AU - Gurney,Howard

AU - Molloy,Mark P.

PY - 2018/5/30

Y1 - 2018/5/30

N2 - Abiraterone acetate is administered as a prodrug to patients with metastatic, castration-resistant prostate cancer (mCRPC) and is readily metabolized into the potent 17a-hydroxylase/17,20-lyase (CYP17) enzyme inhibitor and androgen receptor inhibitor abiraterone and Δ(4)-abiraterone (D4A), respectively. To investigate pharmacokinetic variability in abiraterone acetate metabolism we developed highly sensitive liquid chromatography/mass spectrometry (LC/MS) assays for the simultaneous quantitation of abiraterone and D4A in human plasma using high-resolution mass spectrometry (HRMS) on an Orbitrap mass spectrometer. This study demonstrates the quantitative performance of HRMS and compares the conventional Parallel Reaction Monitoring (PRM) mode of quantitation with the unconventional Full scan MS mode conducted at high resolution ( > 70,000 resolution). The use of HRMS for quantitation of abiraterone and D4A yielded assays that were linear over a broad concentration range (0.074–509.6 ng/mL for abiraterone; 0.075–59.93 ng/mL for D4A) in both Full scan MS and PRM modes. The assay precision for abiraterone and D4A was below 5% in PRM mode and 7% in Full scan MS mode. Accuracies fell within 98–107% for abiraterone and 104–112% for D4A in PRM mode, and 96–116% for abiraterone and 96–105% for D4A in Full scan MS mode, each meeting the acceptance criteria of FDA approved guidelines for bioanalytical methods The PRM analysis of abiraterone and D4A provided high specificity and reduced background interference, however the Full scan MS detection at a resolution of 70,000 was advantageous in that it required minimal optimization, was simple to implement, yielded comparable quantitative characteristics to PRM and the data is useful for re-analysis. Use of the assays were demonstrated for quantitation of these metabolites in steady state trough level plasma of seventeen (17) patients with mCRPC, demonstrating the inter-patient variability of up to 10-fold concentration.

AB - Abiraterone acetate is administered as a prodrug to patients with metastatic, castration-resistant prostate cancer (mCRPC) and is readily metabolized into the potent 17a-hydroxylase/17,20-lyase (CYP17) enzyme inhibitor and androgen receptor inhibitor abiraterone and Δ(4)-abiraterone (D4A), respectively. To investigate pharmacokinetic variability in abiraterone acetate metabolism we developed highly sensitive liquid chromatography/mass spectrometry (LC/MS) assays for the simultaneous quantitation of abiraterone and D4A in human plasma using high-resolution mass spectrometry (HRMS) on an Orbitrap mass spectrometer. This study demonstrates the quantitative performance of HRMS and compares the conventional Parallel Reaction Monitoring (PRM) mode of quantitation with the unconventional Full scan MS mode conducted at high resolution ( > 70,000 resolution). The use of HRMS for quantitation of abiraterone and D4A yielded assays that were linear over a broad concentration range (0.074–509.6 ng/mL for abiraterone; 0.075–59.93 ng/mL for D4A) in both Full scan MS and PRM modes. The assay precision for abiraterone and D4A was below 5% in PRM mode and 7% in Full scan MS mode. Accuracies fell within 98–107% for abiraterone and 104–112% for D4A in PRM mode, and 96–116% for abiraterone and 96–105% for D4A in Full scan MS mode, each meeting the acceptance criteria of FDA approved guidelines for bioanalytical methods The PRM analysis of abiraterone and D4A provided high specificity and reduced background interference, however the Full scan MS detection at a resolution of 70,000 was advantageous in that it required minimal optimization, was simple to implement, yielded comparable quantitative characteristics to PRM and the data is useful for re-analysis. Use of the assays were demonstrated for quantitation of these metabolites in steady state trough level plasma of seventeen (17) patients with mCRPC, demonstrating the inter-patient variability of up to 10-fold concentration.

KW - abiraterone

KW - high-resolution mass spectrometry

KW - metabolomics

KW - pharmacokinetics

KW - prostate cancer

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U2 - 10.1016/j.jpba.2018.03.012

DO - 10.1016/j.jpba.2018.03.012

M3 - Article

VL - 154

SP - 66

EP - 74

JO - Journal of Pharmaceutical and Biomedical Analysis

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JF - Journal of Pharmaceutical and Biomedical Analysis

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