title: Preclinical Pharmacokinetics, Tissue Distribution, and Plasma Protein Binding of Sodium (±)-5-Bromo-2-(α-Hydroxypentyl) Benzoate (BZP), an Innovative Potent Anti-ischemic Stroke Agent.
abstract: 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.
authors: Institute of Clinical Pharmacology, Zhengzhou UniversityHenan, China; Department of Pharmacy, The First Affiliated Hospital of Zhengzhou UniversityHenan, China.
authors: Xin
authors: X
authors: Tian
authors: Institute of Clinical Pharmacology, Zhengzhou University Henan, China.
authors: Hong-Meng
authors: HM
authors: Li
authors: Institute of Clinical Pharmacology, Zhengzhou University Henan, China.
authors: Jing-Yao
authors: JY
authors: Wei
authors: College of Chemistry and Molecular Engineering, Zhengzhou University Zhengzhou, China.
authors: Bing-Jie
authors: BJ
authors: Liu
authors: College of Chemistry and Molecular Engineering, Zhengzhou University Zhengzhou, China.
authors: Yu-Hai
authors: YH
authors: Zhang
authors: Institute of Clinical Pharmacology, Zhengzhou University Henan, China.
authors: Gao-Ju
authors: GJ
authors: Wang
authors: College of Chemistry and Molecular Engineering, Zhengzhou University Zhengzhou, China.
authors: Jun-Biao
authors: JB
authors: Chang
authors: Institute of Clinical Pharmacology, Zhengzhou University Henan, China.
authors: Hai-Ling
authors: HL
authors: Qiao
keywords: BZP; Br-NBP; metabolite; pharmacokinetics; plasma protein binding; tissue distribution