Development, validation and application of a novel liquid chromatography tandem mass spectrometry assay measuring uracil, 5,6-dihydrouracil, 5-fluorouracil, 5,6-dihydro-5-fluorouracil, α-fluoro-β-ureidopropionic acid and α-fluoro-β-alanine in human plasma

Journal of Pharmaceutical and Biomedical Analysis
Ottiniel ChavaniPeter M George

Abstract

The plasma 5,6-dihydrouracil/uracil (UH2/U) ratio is a possible phenotypic marker of dihydropyrimidine dehydrogenase (DPD) activity, hence an index of 5-fluorouracil (5-FU) response and toxicity. Studies have re-affirmed the value of 5-FU and 5,6-dihydro-5-fluorouracil (FUH2) for therapeutic drug monitoring (TDM). However, FUH2 has limited stability in plasma, necessitating expedited plasma separation and freezing, where routine compliance may not be easy. The metabolites α-fluoro-β-ureidopropionic acid (FUPA) and α-fluoro-β-alanine (FβAL) are stable in plasma and are probable candidates for TDM. This paper describes development, validation and application of an LC-MS/MS assay quantifying U, UH2, 5-FU, FUH2, FUPA and FβAL in human plasma. Extraction was by salt-assisted liquid-liquid extraction (LLE) in two-stages with pH adjustment. The supernatants were mixed, dried and reconstituted. Analytes were resolved on the Luna PFP (2) (150×2.00mm, 3μ) column by gradient elution and analyzed by tandem mass spectrometry via electrospray ionisation in positive polarity. The analytical response was linear (r2≥0.99) in the concentration (ng/mL) ranges: 50-10 000 for FβAL and FUH2, 50-5 000 for FUPA, 50-100 000 for 5-FU, 5-200 for U and 10...Continue Reading

Citations

Nov 20, 2018·Expert Opinion on Drug Metabolism & Toxicology·Françoise GoirandAntonin Schmitt
Mar 15, 2020·Journal of Chromatography. B, Analytical Technologies in the Biomedical and Life Sciences·Tiphaine RobinSouleiman El Balkhi

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