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.