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⯵m, 2.1â¯mmâ¯×â¯150â¯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 (r2â¯>â¯0.99) over the ranges of 50-8000â¯ng/mL for MDH-7 and 10-2000â¯ng/mL for 5-FU, respectively. The lower limit of quantitations (LLOQs) was 50â¯ng/mL (MDH-7) and 10â¯ng/mL (5-FU) with relative standard deviation (RSD)â¯<â¯13.0%. The proposed method was successfully applied to simultaneous assessment of pharmacokinetic drug-drug interaction between MDH-7 and 5-FU in rats.
Subject(s)
Antimetabolites, Antineoplastic/blood , Chromatography, Liquid/methods , Cytosine/analogs & derivatives , Fluorouracil/blood , Pyrimidine Nucleosides/blood , Tandem Mass Spectrometry/methods , Animals , Antimetabolites, Antineoplastic/chemistry , Antimetabolites, Antineoplastic/pharmacokinetics , Cytosine/blood , Cytosine/chemistry , Cytosine/pharmacokinetics , Drug Stability , Female , Fluorouracil/chemistry , Fluorouracil/pharmacokinetics , Linear Models , Male , Pyrimidine Nucleosides/chemistry , Pyrimidine Nucleosides/pharmacokinetics , Rats , Rats, Sprague-Dawley , Reproducibility of Results , Sensitivity and SpecificityABSTRACT
Andrographolide (1) is a major diterpene lactone exhibiting anti-inflammatory effects and is found in the plant Andrographis paniculata (Burm. f) Nees, which is widely used in Traditional Chinese Medicine. Synthesis of more effective drugs from andrographolide is very interesting and can prove to be highly useful. In this study, we investigated the anti-inflammatory effects of andrographolide and its derivatives (compounds 2-6) through dimethylbenzene-induced ear edema in mice. Substances under study were administrated intragastrically and the structure-activity relationship was analyzed. Results showed that compounds 5 and 6 significantly inhibited ear edema compared with compound 1 (p<0.05), indicating that the introduction of p-Chlorobenzylidene to C-15 of compound 2 enhances the anti-inflammatory effect. Moreover, compound 6 exhibited the strongest anti-inflammatory effect against ear edema in mice (79.4%; 1.35 mmol/kg, ig) and paw edema in rats (50.4%; 0.90 mmol/kg, ig). In addition, compound 6 significantly (p<0.05) inhibited granuloma formation and reduced the increase in vascular permeability induced by peritoneal injection of 0.6% acetic acid solution in mice. Findings indicate that compound 6 exerts its enhanced anti-inflammatory effects by decreasing serum iNOS activity, NO production, and PGE(2) production.