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.
Highlights
Ischemic stroke accounts for 75–85% of all the strokes occurring annually in China and approximately 5.7 million people are estimated to die of acute ischemic stroke per year worldwide (Bravata et al, 2007; Broussalis et al, 2012)
The mean the peak plasma concentration (Cmax) and AUC0–t values of sodium-5-bromo-2-(α-hydroxypentyl) benzoate (BZP) were linearly related to the dose in the range of 3–12 mg/kg
As for other major pharmacokinetic parameters such as t1/2z, total plasma clearance (CLz), and volume of distribution (Vz), a significant difference was observed between the low dose group (3 mg/kg) and middle dose group (6 mg/kg), while no difference was found between the middle dose group (6 mg/kg) and high dose group (12 mg/kg)
Summary
Ischemic stroke accounts for 75–85% of all the strokes occurring annually in China and approximately 5.7 million people are estimated to die of acute ischemic stroke per year worldwide (Bravata et al, 2007; Broussalis et al, 2012). 1-3-n-butylphthalide (NBP), first isolated from the seeds of celery, was a potent, and widely used drug for the treatment of ischemic stroke in clinic, and it was approved in form of soft capsule and infusion drip by the China Food and Drug Administration (CFDA) in 2004 (Zhang et al, 2012; Yang et al, 2015; Zhao et al, 2016). About 28% of the patients had adverse events (AE) such as cerebral hemorrhage, erythra, pneumonia, and liver dysfunction, which may interrupt clinical uses of NBP. The bioavailability being as low as 15% limits the application of NBP capsule in acute ischemic stroke patients (Cui et al, 2013)
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