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Simultaneous pharmacokinetic and pharmacodynamic analysis of 5α-reductase inhibitors and androgens by liquid chromatography tandem mass spectrometry

Lookup NU author(s): Professor Brian Walker

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Abstract

© 2014 The Authors. Published by Elsevier B.V.Benign prostatic hyperplasia and prostate cancer can be treated with the 5α-reductase inhibitors, finasteride and dutasteride, when pharmacodynamic biomarkers are useful in assessing response. A novel method was developed to measure the substrates and products of 5α-reductases (testosterone, 5α-dihydrotestosterone (DHT), androstenedione) and finasteride and dutasteride simultaneously by liquid chromatography tandem mass spectrometry, using an ABSciex QTRAP® 5500, with a Waters Acquity™ UPLC. Analytes were extracted from serum (500 μL) via solid-phase extraction (Oasis® HLB), with 13C3-labelled androgens and d9-finasteride included as internal standards. Analytes were separated on a Kinetex C18 column (150 x 3 mm, 2.6 μm), using a gradient run of 19 min. Temporal resolution of analytes from naturally occurring isomers and mass +2 isotopomers was ensured. Protonated molecular ions were detected in atmospheric pressure chemical ionisation mode and source conditions optimised for DHT, the least abundant analyte. Multiple reaction monitoring was performed as follows: testosterone (m/z 289→97), DHT (m/z 291→255), androstenedione (m/z 287→97), dutasteride (m/z 529→461), finasteride (m/z 373→317). Validation parameters (intra- and inter-assay precision and accuracy, linearity, limits of quantitation) were within acceptable ranges and biological extracts were stable for 28 days. Finally the method was employed in men treated with finasteride or dutasteride; levels of DHT were lowered by both drugs and furthermore the substrate concentrations increased.


Publication metadata

Author(s): Upreti R, Naredo G, Faqehi AMM, Hughes KA, Stewart LH, Walker BR, Homer NZM, Andrew R

Publication type: Article

Publication status: Published

Journal: Talanta

Year: 2015

Volume: 131

Pages: 728-735

Print publication date: 01/01/2015

Online publication date: 14/08/2014

Acceptance date: 30/07/2014

ISSN (print): 0039-9140

ISSN (electronic): 1873-3573

Publisher: Elsevier

URL: https://doi.org/10.1016/j.talanta.2014.07.087

DOI: 10.1016/j.talanta.2014.07.087

PubMed id: 25281165


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