Tian Xin, Li Hong-Meng, Wei Jing-Yao, Liu Bing-Jie, Zhang Yu-Hai, Wang Gao-Ju, Chang Jun-Biao, Qiao Hai-Ling
Institute of Clinical Pharmacology, Zhengzhou UniversityHenan, China; Department of Pharmacy, The First Affiliated Hospital of Zhengzhou UniversityHenan, China.
Institute of Clinical Pharmacology, Zhengzhou University Henan, China.
Front Pharmacol. 2016 Aug 18;7:255. doi: 10.3389/fphar.2016.00255. eCollection 2016.
Sodium (±)-5-bromo-2-(α-hydroxypentyl) benzoate (BZP) is a potential cardiovascular drug and exerts potent neuroprotective effect against transient and long-term ischemic stroke in rats. BZP could convert into 3-butyl-6-bromo-1(3H)-isobenzofuranone (Br-NBP) in vitro and in vivo. However, the pharmacokinetic profiles of BZP and Br-NBP still have not been evaluated. For the purpose of investigating the pharmacokinetic profiles, tissue distribution, and plasma protein binding of BZP and Br-NBP, a rapid, sensitive, and specific method based on liquid chromatography coupled to mass spectrometry (LC-MS/MS) has been developed for determination of BZP and Br-NBP in biological samples. The results indicated that BZP and Br-NBP showed a short elimination half-life, and pharmacokinetic profile in rats (3, 6, and 12 mg/kg; i.v.) and beagle dogs (1, 2, and 4 mg/kg; i.v.gtt) were obtained after single dosing of BZP. After multiple dosing of BZP, there was no significant accumulation of BZP and Br-NBP in the plasma of rats and beagle dogs. Following i.v. single dose (6 mg/kg) of BZP to rats, BZP and Br-NBP were distributed rapidly into all tissues examined, with the highest concentrations of BZP and Br-NBP in lung and kidney, respectively. The brain distribution of Br-NBP in middle cerebral artery occlusion (MCAO) rats was more than in normal rats (P < 0.05). The plasma protein binding degree of BZP at three concentrations (8000, 20,000, and 80,000 ng/mL) from rat, beagle dog, and human plasma were 98.1-98.7, 88.9-92.7, and 74.8-83.7% respectively. In conclusion, both BZP and Br-NBP showed short half-life, good dose-linear pharmacokinetic profile, wide tissue distribution, and different degree protein binding to various species plasma. This was the first preclinical pharmacokinetic investigation of BZP and Br-NBP in both rats and beagle dogs, which provided vital guidance for further preclinical research and the subsequent clinical trials.
（±）-5-溴-2-（α-羟基戊基）苯甲酸钠（BZP）是一种潜在的心血管药物，对大鼠短暂性和长期缺血性中风具有强大的神经保护作用。BZP在体内外均可转化为3-丁基-6-溴-1（3H）-异苯并呋喃酮（Br-NBP）。然而，BZP和Br-NBP的药代动力学特征仍未得到评估。为了研究BZP和Br-NBP的药代动力学特征、组织分布及血浆蛋白结合情况，已开发出一种基于液相色谱-质谱联用（LC-MS/MS）的快速、灵敏且特异的方法，用于测定生物样品中的BZP和Br-NBP。结果表明，BZP和Br-NBP的消除半衰期较短，单次静脉注射BZP（大鼠3、6和12 mg/kg；比格犬1、2和4 mg/kg）后获得了大鼠和比格犬的药代动力学特征。多次给药BZP后，大鼠和比格犬血浆中BZP和Br-NBP均无明显蓄积。给大鼠静脉单次注射（6 mg/kg）BZP后，BZP和Br-NBP迅速分布到所有检测组织中，BZP和Br-NBP分别在肺和肾中浓度最高。大脑中动脉闭塞（MCAO）大鼠中Br-NBP的脑部分布高于正常大鼠（P < 0.05）。大鼠、比格犬和人血浆中三种浓度（8000、20000和80000 ng/mL）的BZP血浆蛋白结合率分别为98.1 - 98.7%、88.9 - 92.7%和74.8 - 83.7%。总之，BZP和Br-NBP均显示出半衰期短、良好的剂量线性药代动力学特征、广泛的组织分布以及与不同物种血浆不同程度的蛋白结合。这是首次在大鼠和比格犬中对BZP和Br-NBP进行的临床前药代动力学研究，为进一步的临床前研究和后续临床试验提供了重要指导。
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