A rapid and sensitive method for determination of dimethyl benzoylphenyl urea in human plasma by using LC/MS/MS

Ming Zhao, Yelena Zabelina, Michelle A. Rudek, Antonio C. Wolff, Sharyn D. Baker

Research output: Contribution to journalArticle

Abstract

Dimethyl benzoylphenyl urea (BPU), a poorly water-soluble benzoylphenyl urea derivative, inhibits tubulin polymerization and causes microtubule depolymerization in vitro with activity against solid tumors. BPU is currently being tested in Phase I clinical trials. A rapid, sensitive and specific method using LC/MS/MS has been developed for the quantitation of BPU in human plasma to perform pharmacokinetic (PK) and pharmacodynamic (PD) studies of BPU administered orally once a week. BPU is extracted from plasma into acetonitrile-n-butylchloride and separated on a Waters X-Terra™ MS C18 (50×2.1 mm, 3.5 μm) column with acetonitrile/water mobile phase (80:20, v/v) containing 0.1% formic acid using isocratic flow at 0.15 ml/min for 5 min. The analyte of interest was monitored by tandem-mass spectrometry with electrospray positive ionization with a cone voltage 15 V for BPU and 30 V for the internal standard, paclitaxel. The detector settings allowed the monitoring of the [MH]+ ion of BPU (m/z 470.3) and the [MH]+ of internal standard paclitaxel (m/z 854.5), with subsequent monitoring of the product ions of BPU (m/z 148.0) and paclitaxel (m/z 286.1). Calibration curves were generated over the range of 0.05-10 ng/ml with values for coefficient of determination of >0.99. The values for precision and accuracy were <20 and ≤15%, respectively. Following administration of BPU 5 mg as a weekly oral dose to a patient with advanced solid tumor malignancies, the maximum plasma concentration was 6.5 ng/ml and concentrations were quantifiable up to 173 h after administration. The lower limit of quantitation (LLOQ) of 0.05 ng/ ml allows for successful measurement of plasma concentrations in patients receiving therapy with BPU as a once weekly oral dose.

Original languageEnglish (US)
Pages (from-to)725-733
Number of pages9
JournalJournal of Pharmaceutical and Biomedical Analysis
Volume33
Issue number4
DOIs
StatePublished - Nov 24 2003

Keywords

  • Dimethyl benzoylphenyl urea (BPU)
  • LC/MS/MS
  • Pharmacokinetics

ASJC Scopus subject areas

  • Analytical Chemistry
  • Pharmaceutical Science
  • Drug Discovery
  • Spectroscopy
  • Clinical Biochemistry

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