Simultaneous determination of the novel anti-tumor candidate drug MDH-7 and 5-fluorouracil in rat plasma by LC-MS/MS: Application to pharmacokinetic interactions

Abstract

MDH-7 (2,3,9-tri-O-acetyl-5,6-dideoxy-1,10-di-[N4'-pentoxycarbonyl-5'-fluoro cytosine]-4-ulose 1,4: 7,10-difuranose-4,8-pyranose) is a novel anti-tumor drug candidate. To study the pharmacokinetic interaction between MDH-7 and 5-fluorouracil (5-FU), a sensitive and rapid liquid chromatography-tandem mass spectrometry (LC-MS/MS) method was developed to simultaneously determine the concentrations of MDH-7 and 5-fluorouracil (5-FU) in rat plasma. Plasma samples were prepared by simple liquid-liquid extraction with ethyl acetate. Chromatographic separation was performed on a Waters XBridge™ C18 column (5 μm, 2.1 mm × 150 mm) with the mobile phase of methanol and H₂O (80:20, v/v). The ESI positive and negative ion switch was operated in the multiple reactions monitoring (MRM) mode. The calibration curves showed good linearity (r² > 0.99) over the ranges of 50-8000 ng/mL for MDH-7 and 10-2000 ng/mL for 5-FU, respectively. The lower limit of quantitations (LLOQs) was 50 ng/mL (MDH-7) and 10 ng/mL (5-FU) with relative standard deviation (RSD) < 13.0%. The proposed method was successfully applied to simultaneous assessment of pharmacokinetic drug-drug interaction between MDH-7 and 5-FU in rats.

Keywords: 5-Fluorouracil; LC-MS/MS; MDH-7; Pharmacokinetics; Rat plasma.