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Objective: To study the blood and brain drug concentration and drug distribution coefficient of lactones in rats after oral administration of Ginkgo biloba extract (GBE). Methods: Blood-brain synchronization microdialysis was used in combination with HPLC-MS/MS inthis study. Probes were buried into rat brain and jugular vein to collect the blood and brain micro dialysis liquid in rats after oral GBE in different periods. The lactones in the dialysate were analyzed by HPLC-MS/MS, and the blood and brain drug concentration was depicted according to the results. Then the drug distribution coefficients of each component in blood and brain (AUCbrain/AUCblood) were calculated. Results: After GBE suspension (600 mg/kg) oral gavaging in the rats, the blood samples and brain samples were obtained and detected by HPLC/MS/MS. Ginkgolides A, B, and C were detected in both blood and in brain, but bilobalide could be detected just in blood. The drug distribution coefficients in the blood and brain (AUCbrain/AUCblood) were as follows: Ginkgolide A was 2.911%, ginkgolide B was 3.126%, and ginkgolide C was 0.337%. Conclusion: Simultaneous multiple microdialysis technique can be used to detect multiple components in different tissues simultaneously. It also has other characteristics, such as continuous sampling on living animals with small sample volume and little tissue damage, which can save animals. In all, simultaneous multiple microdialysis could be a good method for exploring the effect components in Chinese medicine and their distribution at effect sides.
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This study aims to prepare nimodipine/tetramethylpyrazine-loaded poly(D, L-lactide-co-glycolide) dual-drug nanoparticles (NMD/TMP-NPs) and investigate pharmacokinetics and brain distribution to evaluate the possibility of enhancing the drug effect of dual-drug nanoparticles. NMD/TMP-NPs were prepared via W/O/W emulsion solvent evaporation. Entrapment efficiency and drug loading of NMD/TMP-NPs were investigated by ultracentrifugation, and drug release behavior in vitro was studied by dialysis method. The pharmacokinetic and brain distribution were studied in SD mice administered intravenously with NMD/TMP-NPs in comparison with NMD-suspension, NMD/TMP-suspension and NMD-NPs, (NMD-NPs+TMP)-suspension. According to the results, the entrapment efficiency and drug loading of NMD were (79.71±0.73)%, (1.74±0.02)%, those of TMP were (40.26±1.51)% and (4.38±0.16)%. The nanoparticles showed the property of sustained release. On the basis of the major parameters for in vivo pharmacokinetic and brain distribution, t1/2β of NMD-suspension, NMD/TMP-suspension and NMD-NPs, (NMD-NPs+TMP)-suspension, NMD/TMP-NPs were (1.097±0.146), (1.055±0.06), (1.950±0.140), (1.860±0.096), (2.497±0.475） h, CL were (0.778±0.098), (1.133±0.111), (0.247±0.023), (0.497±0.040), (0.297±0.024) h•L-1, AUC0-t in rat plasma were (514.218±60.383), (352.916±33.691), (1 618.429±240.198), (804.110±75.804), (1 349.058±215.497) μg•h•L⁻¹, respectively, and AUC0-t in brain were 0.301 9, 0.624 8, 1.068 6, 1.313 0, 1.046 5 mg•h•L⁻¹, respectively. According to the in vivo study, the pharmacokinetic behavior of NMD were markedly prolonged by adding TMP or prepared dual-drug nanoparticles.
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OBJECTIVE:To prepare borneol-puerarin liposomes,and to investigate its brain-targeting. METHODS:Film dis-persion ultrasonic method was used to prepare borneol-puerarin liposomes. The morphology of liposomes was observed by TEM;the particle size and Zeta potential were measured by laser particle size analyzer;the entrapment efficiency were measured by sepha-dex gel filtration method. Compared with Puerarin injection,brain-targeting of borneol-puerarin liposomes and puerarin liposomes via intravenous injection of mice tail was studied with relative intake rate and peak concentration ratio. RESULTS:Borneol-puerarin liposomes were spherical or quasi-circular;its mean particle size,polydispersity index and Zeta potential were 226 nm,0.263 and-21.3 mV respectively. The entrapment efficiency were(65.32±2.13)%. Compared with Puerarin injection,relative intake rate of puerarin liposome and borneol-puerarin liposome were 1.68 and 2.58,and peak concentration ratio were 1.15 and 1.42. CONCLU-SIONS:Brain-targeted borneol-puerarin liposomes are prepared successfully.
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Objective To develop a steady-state brain distribution model in rats and to assess the blood brain barrier (BBB) penetration of antipyrine, atenolol and a group of ZZB candidate compounds. Methods Antipyrine, atenolol and ZZB compounds were administered to rats by an initial iv bolus dose (loading dose) followed by iv infusion at a constant rate for 30-40 min to reach steady-state plasma kinetics. The blood and brain tissue samples were then collected. The steady-state concentrations of the samples were measured by LC-MS/MS. The steady-state ratio of brain to plasma concentration (Kp) was calculated. The drugs and candidate compounds were also tested with Caco-2 cell model and the apparent bidirectional transport permeability coefficient (Papp) was obtained. Results Antipyrine and atenolol were known as drugs with high and low BBB penetration properties respectively. The mean brain concentrations of antipyrine and atenolol at steady-state were (2561 ± 125) and (20.1 ±0.8)ng/g with the Kp values of 0.93 ± 0.04 and 0.015 ± 0.002, respectively. The Kp value of antipyrine was about 60 folds higher than that of atenolol. Despite the similar structures of ZZB compounds, the Kp values were varied in the range from 0.044 to 6.41. The Kp values were not correlated with Papp values yielded from Caco-2 cell model. Conclusion The established rat steady-state brain distribution model is simple, reliable and could significantly reduce the animal use. It is a practical in vivo model for assessment of BBB penetration of drugs.Key words].
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Sai-Luo-Tong (SLT) is a compound preparation composed of ginseng, ginkgo and saffron for the treatment of vascular dementia. In order to identify its material foundation and provide evidence for therapeutic regimen, the plasma concentration, pharmacokinetics and brain distribution of ginkgolides were investigated after intragastric ad-ministration of SLT. An LC-MS/MS method was developed for the determination of 4 ginkgolides in rat plasma and brain simultaneously. Statistical analysis of obtained data demonstrated that the method had achieved the desired lin-earity, precision, accuracy and sensitivity. The results showed that after administration of SLT at the dose of 60 mg·kg-1, 4 ginkgolides were all absorbed into systemic circulation with AUC value in the order of bilobalide B (BB) >ginkgolide A (GA) > ginkgolide B (GB) > ginkgolide C (GC). All ginkgolides exhibited short half lives less than 2.8 h among which BB showed the shortest t1/2 of 1.61 h. The determination of brain distribution at different time after dos-ing revealed ginkgolides entered into brain promptly dominated by GA and BB. The concentrations of 4 ginkgolides in brain were much lower than these in plasma and declined along with time rapidly. It was concluded that ginkgolides can be absorbed in blood and penetrated into brain rapidly. GA, BB and GB might be main components which effect both periphery and brain collectively by means of their specific mechanism to achieve the therapeutic efficacy on vascular dementia of SLT.
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OBJECTIVE: To prepare nimodipine/tetramethylpyrazine-loaded poly[poly (lactic-co-glycolic acid), PLGA] dual-drug nanoparticles (nimodipine/tetramethylpyrazine-PLGA-nanoparticles, NMD/TMP-PLGA-NPs), and investigate the in vitro release behavior and brain distribution. METHODS: NMD/TMP-PLGA-NPs were prepared by optimized emulsion solvent evaporation method with PLGA as a carrier material; the morphology of NMD/TMP-PLGA-NPs was observed by transmission electron microscope; the mean particle size, particle size distribution and Zeta potential were measured by laser particle size analyzer; the entrapment efficiency and drug loading were measured by ultracentrifugation; the in vitro release behavior was studied by dialysis; the brain distribution was compared with NMD-suspension and NMD-PLGA-NPs. RESULTS: The NMD/TMP-PLGA-NPs were spherical; the mean particle size, particle size distribution and Zeta potential of NPs were (631.60±3.20) nm, (0.097±0.007), (-29.25±1.87) mV, respective-ly. The entrapment efficiency and drug loading of NMD were (76.25±1.18)% and (1.24±0.01)%, while those of TMP were (39.30±1.00)% and (6.34±0.11)%, respectively. The profiles of in vitro release had the features of sustained release. The ALC0→t of NMD-suspension, NMD-PLGA-NPs and NMD/TMP-PLGA-NPs were 0.2683, 0.4596 and 0.8815 μg·min·mL-1, and the addition of TMP promoted the reach of highest brain concentration. CONCLUSION: NMD/TMP-PLGA-NPs are prepared successfully and show sustained-release in vitro, and the distribution of NMD into brain was increased significantly with the addition of TMP.