Department of Pharmaceutics, College of Pharmacy, Jinan University, Guangzhou, PR China.
PLoS One. 2013 Jul 30;8(7):e70189. doi: 10.1371/journal.pone.0070189. Print 2013.
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.
依诺昔酮是一种有效的 NADPH 氧化酶抑制剂，广泛应用于炎症相关疾病、哮喘和心血管疾病等疾病的研究。在我们最近的研究中，一种新型依诺昔酮硝酮衍生物 AN-1，在 RAW 264.7 巨噬细胞中对叔丁基过氧化物（t-BHP）诱导的氧化损伤和 gp91（phox）亚单位的高表达具有很强的抑制作用，并对脂多糖（LPS）诱导的大鼠急性肺损伤表现出有希望的临床前保护作用。在这项工作中，我们研究了 AN-1 在单次静脉和灌胃给药的 Sprague-Dawley 大鼠中的药代动力学行为，以便进一步开发。此外，即使对其药理作用进行了广泛评估，依诺昔酮的药代动力学仍缺乏研究。同时还比较了母体依诺昔酮的药代动力学。建立并验证了一种简单的 HPLC 方法，用于测定大鼠血浆中的 AN-1 和依诺昔酮。色谱分离在 Agilent HC-C18 柱（250mm×4.6mm，5μm）上实现，以甲醇和水（53∶47，v/v）为流动相，UV 检测波长为 279nm。AN-1 的浓度范围为 0.1-500μg/mL，依诺昔酮的浓度范围为 0.2-100μg/mL，均具有良好的线性关系。绝对回收率、精密度和准确度令人满意。与母体化合物依诺昔酮相比，等摩尔静脉注射（0.302mmol/kg）后，AN-1 的 T1/2（AN-1 为 179.8min，依诺昔酮为 6.1min）和 AUC0-t（AN-1 为 61.89mmol/L·min，依诺昔酮为 2.49mmol/L·min）均明显延长。口服 AN-1 的绝对生物利用度为 78%，而依诺昔酮仅为 2.8%。新型硝酮衍生物 AN-1 的药效学结果显著改善了其药代动力学行为。
