HOMEPRODUCTSCOMPANYCONTACTFAQResearchDictionaryPharmaSign Up FREE or Login

Improvement of pharmacokinetics behavior of apocynin by nitrone derivatization: comparative pharmacokinetics of nitrone-apocynin and its parent apocynin in rats.

Abstract
Apocynin, a potent inhibitor of NADPH-oxidase, was widely studied for activities in diseases such as inflammation-mediated disorders, asthma and cardiovascular diseases. In our recent study, a novel nitrone derivative of apocynin, AN-1, demonstrated potent inhibition to oxidative injury and to high expression of gp91(phox) subunit of NADPH-oxidase induced by tert-butyl hydroperoxide (t-BHP) in RAW 264.7 macrophage cells, and displayed promising preclinical protective effect against lipopolysaccharide (LPS)-induced acute lung injury in rats. In this work, the pharmacokinetic behaviors of AN-1 in Sprague-Dawley rats with single intravenous and intragastric doses were investigated for further development. Furthermore, apocynin's pharmacokinetics remain lacking, even though its pharmacological action has been extensively evaluated. The pharmacokinetics of parent apocynin were also comparatively characterized. A simple HPLC method was developed and validated to determine both AN-1 and apocynin in rat plasma. The chromatographic separation was achieved on an Agilent HC-C18 column (250 mm×4.6 mm, 5 µm) at an isocratic flow rate of 1.0 mL/min, with the mobile phase of methanol and water (53∶47, v/v) and the UV detection set at 279 nm. Good linearity was established over the concentration range of 0.1-500 µg/mL for AN-1 and 0.2-100 µg/mL for apocynin. The absolute recovery, precision and accuracy were satisfactory. Compared with the parent compound apocynin, AN-1 yielded a much longer T1/2 (AN-1 179.8 min, apocynin 6.1 min) and higher AUC0-t (AN-1 61.89 mmol/L·min, apocynin 2.49 mmol/L·min) after equimolar intravenous dosing (0.302 mmol/kg). The absolute bioavailability of oral AN-1 was 78%, but that of apocynin was only 2.8%. The significant improvement of pharmacokinetic behavior might be accounted for the effective pharmacodynamic results we documented for the novel nitrone derivative AN-1.
AuthorsKaiyu Wang, Linlin Li, Yan Song, Xiaocui Ye, Shaolian Fu, Jie Jiang, Sha Li
JournalPloS one (PLoS One) Vol. 8 Issue 7 Pg. e70189 ( 2013) ISSN: 1932-6203 [Electronic] United States
PMID23936162 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
Chemical References
  • Acetophenones
  • Enzyme Inhibitors
  • acetovanillone
Topics
  • Acetophenones (chemistry, pharmacokinetics)
  • Animals
  • Biological Availability
  • Chromatography, High Pressure Liquid
  • Enzyme Inhibitors (chemistry, pharmacokinetics)
  • Male
  • Mass Spectrometry
  • Mice
  • Rats
  • Reproducibility of Results

Join CureHunter, for free Research Interface BASIC access!

Take advantage of free CureHunter research engine access to explore the best drug and treatment options for any disease. Find out why thousands of doctors, pharma researchers and patient activists around the world use CureHunter every day.
Realize the full power of the drug-disease research graph!


Choose Username:
Email:
Password:
Verify Password:
Enter Code Shown: