Shouying Du

Enhancing effect of natural borneol on the absorption of geniposide in rat via intranasal administration

Both geniposide (Ge) and natural borneol (NB) are bioactive substances derived from traditional Chinese herbs. The effect of NB on the pharmacokinetics of Ge in rat via intranasal administration was investigated. The concentrations of Ge in plasma were determined by reversed-phase high-performance liquid chromatography (HPLC) after intranasal administration of Ge (4 mg/kg) alone and combined with different doses (0.08, 0.8, and 8 mg/kg) of NB. The intravenous administration was given as a reference (4 mg/kg of Ge and 8 mg/kg of NB). Compared with the intravenous administration, the absolute bioavailability of Ge was 76.14% through intranasal administration combined with NB. Compared with the intranasal administration of Ge alone, Ge could be absorbed rapidly in the nasal cavity combined with NB; the peak time of Ge in the plasma became shorter (3–5 min vs. 40 min); the peak concentration became higher (1.32–4.25 μg/ml vs. 0.67 μg/ml); and, the relative bioavailability of Ge combined with NB was 90.3%–237.8%. The enhancing effect was attenuated as the dose of NB decreased. The results indicated that NB can accelerate the absorption of Ge dose-dependently in the nasal cavity.

Bioavailability and Brain-Targeting of Geniposide in Gardenia-Borneol Co-Compound by Different Administration Routes in Mice

Both geniposide (Ge) and borneol (Bo) are bioactive substances derived from traditional Chinese medicine. Injections containing co-compound of Gardenia-Borneol are widely used for stroke treatment in China, such as “Xingnaojing” multi-component injection. As more and more adverse reactions (especially drug allergy) were reported, it is urgent to find more effective and safer routes of administration for such kinds of medicines. In this paper, bioavailabilities and brain-target effects of geniposide in Gardenia-Borneol co-compound through different administration routes in mice were investigated. Geniposide concentrations in plasma and in brain of mice were determined by reversed-phase high-performance liquid chromatography. The pharmacokinetics parameters of intranasal (i.n.) and intragastric (i.g.) administration were compared with intravenous (i.v.) administration. The bioavailabilities of Ge were 85.38% and 28.76% for i.n. and i.g. while Tmax were 1 min and 30 min. Cmax were 21.881 ± 5.398, 1.914 ± 0.327 and 42.410 ± 6.268 μg/mL for i.n., i.g. and i.v., respectively. The AUC of Ge in brain were 32413.6 ± 4573.9, 6440.1 ± 863.7 and 37270.5 ± 4160.6 ng/g·min for i.n., i.g. and i.v., respectively. The drug target indexes (DTI) were 1.02 and 0.60 for i.n. and i.g. The results demonstrated that geniposide could be absorbed promptly and thoroughly by i.n. administration in mice and basically transported into the brain though blood vessel passways.

Simultaneous determination of notoginsenoside R1, ginsenoside Rg1, ginsenoside Re and 20(S) protopanaxatriol in beagle dog plasma by ultra high performance liquid mass spectrometry after oral administration of a Panax notoginseng saponin preparation

20(S) protopanaxatriol is the main metabolite of notoginsenoside R1, ginsenoside Rg1, ginsenoside Re in Panax notoginseng and has significant activities. A ultra high performance liquid mass spectrometry method has been developed and validated for the simultaneous determination of notoginsenoside R₁ (R1), ginsenoside Rg₁ (Rg₁), ginsenoside Re (Re) and 20(S) protopanaxatriol (PPT) in beagle dog plasma after oral administration of a Panax notoginseng saponin preparation. After the addition of the internal standard (digoxin), plasma samples were subjected to liquid-liquid extraction with acetone and methanol and separated on a 100 × 2.1 mm ACQUITY 1.7 μm C₁₈ column (Waters, USA), with acetonitrile and water as the mobile phase, within a runtime of 7.0 min. The analytes were detected without interference in Selected Reaction Monitoring mode with a change in the electrospray ionization from positive to negative. The detection limits were 0.01 to 0.04 mg/L and the calibration curves of the peak areas for the four ingredients were linear over four orders of magnitude with a correlation coefficient greater than 0.9957. The intra-day and inter-day precision values (relative standard deviation, RSD, %) were within 10.25% and 13.51%, respectively, and the accuracy (relative error, RE, %) was less than 7.81%. The validated method was successfully applied to a comparative pharmacokinetic study of four saponins in beagle dogs after oral administration of a Panax Notoginseng Saponins preparation. The pharmacokinetic parameters were calculated with DAS 3.20. The Tmax and Cmax values indicate a dose-dose relationship between the saponins (R1, Rg1, and Re) and their sapogenin (PPT).

Enhancing Effect of Borneol and Muscone on Geniposide Transport across the Human Nasal Epithelial Cell Monolayer

Geniposide is widely used in the treatment of cerebral ischemic stroke and cerebrovascular diseases for its anti-thrombotic and anti-inflammatory effects. Recent studies demonstrated that geniposide could be absorbed promptly and thoroughly by intranasal administration in mice and basically transported into the brain. Here, we explored its transport mechanism and the effect of borneol and muscone on its transport by human nasal epithelial cell (HNEC) monolayer. The cytotoxicity of geniposide, borneol, muscone and their combinations on HNECs was evaluated by the MTT assay. Transcellular transport of geniposide and the influence of borneol and muscone were studied using the HNEC monolayer. Immunostaining and transepithelial electrical resistance were measured to assess the integrity of the monolayer. The membrane fluidity of HNEC was evaluated by fluorescence recovery after photobleaching. Geniposide showed relatively poor absorption in the HNEC monolayer and it was not a P-gp substrate. Geniposide transport in both directions significantly increased when co-administrated with increasing concentrations of borneol and muscone. The enhancing effect of borneol and muscone on geniposide transport across the HNEC may be attributed to the significant enhancement on cell membrane fluidity, disassembly effect on tight junction integrity and the process was reversible. These results indicated that intranasal administration has good potential to treat cerebrovascular diseases.

Brain distribution pharmacokinetics and integrated pharmacokinetics of Panax Notoginsenoside R1, Ginsenosides Rg1, Rb1, Re and Rd in rats after intranasal administration of Panax Notoginseng Saponins assessed by UPLC/MS/MS

Panax notoginseng saponins (PNS) constitute the main active components of a traditional Chinese medicine, Panax notoginseng (Burk.) F.H. Chen (Sanqi). To investigate brain distribution of Panax Notoginsenoside R1, Ginsenosides Rg1, Rb1, Re, and Rd, and the integrated PNS in rats, their contents in cortex, striatum, hypothalamus, medulla oblongata, hippocampus and olfactory bulb were simultaneously measured by UPLC-MS/MS. Sample preparation was carried out by the protein precipitation technique with an internal Digoxin standard. The method described here was highly efficient, with short run time, excellent specificity and sensitivity, and successfully applied for pharmacokinetics studies. NGR1, GRg1, GRb1, GRe and GRd from PNS have been detected in all six brain regions studied and quantified accurately. These findings provide more insight for further understanding of the main ways from the nasal cavity to brain as well as the migration of nasally applied drugs into the CNS parenchyma.

Comparative pharmacokinetic studies of borneol in mouse plasma and brain by different administrations

Borneol, a monoterpenoid alcohol, is used widely, particularly in combined formulas for preventing and curing cardiovascular and cerebrovascular diseases in traditional Chinese medicine. In order to understand the blood and brain pharmacokinetics after intravenous, intranasal, or oral administration and to investigate the superiority and feasibility of intranasal administration, a simple gas chromatographic (GC) method with flame ionization detection (FID) was developed for the quantification of borneol. Blood samples and brain were collected from mice at 1, 3, 5, 10, 20, 30, 60, 90, and 120 min after intravenous, intranasal, or oral administration of borneol at a dosage of 30.0 mg/kg. Sample preparations were carried out by liquid-liquid extraction with an internal standard solution of octadecane. The pharmacokinetic parameters were calculated by the software of Kinetica. The calibration curves were linear in the range of 0.11–84.24 μg/ml and 0.16–63.18 μg/g for borneol in plasma and brain, respectively. The methodological and extraction recoveries were both in the range of 85%–115%. The intra-day and inter-day variabilities for plasma and brain samples were ≤5.00% relative standard deviation (RSD). The absolute bioavailabilities F of intranasal and oral administrations were 90.68% and 42.99%. The relative brain targeted coefficients Re of intranasal and oral administrations were 68.37% and 38.40%. The GC-FID method developed could be applied to determination and pharmacokinetic study. The borneol from injection was distributed and metabolized fast without absorption process. The borneol from oral administration was distributed more slowly and had the lowest absolute bioavailability. Nasal administration of borneol was quickly absorbed into the blood and brain, was easy to use and had a greater safety than infection, which makes it worthy of further development as an administration route for encephalopathy treatment.

Effect of Panax notoginseng saponins on the pharmacokinetics of aspirin in rats

Aspirin (ASA) is widely used to treat fever, pain, inflammation and cerebral infarction in clinic. Panax Notoginseng Saponins (PNS) is the extracts of Panax Notoginseng (PN)-a traditional Chinese medicine extensively used in cardiovascular diseases. Panax notoginseng saponins and ASA are both widely used to treat cerebral infarction in China. Good results in clinical practice have been achieved when the two drugs were taken together. To investigate the effect of PNS on ASA in vivo, the concentrations of salicylic acid (SA) in blood were measured after oral administration of ASA or ASA combined with PNS by UPLC-MS/MS. Sample preparation was carried out by the protein precipitation technique with an internal Saikosaponin A standard. The separation of two components was achieved by using an ACQUITY UPLC ®BEH C18 Column (1.7μm 2.1×100mm) by gradient elution using water (containing 0.2% formic acid) and acetonitrile (containing 0.2% formic acid) as the mobile phase at a flow rate of 0.2mL/min. The pharmacokinetic parameters were determined by using non-compartmental analysis. The results suggested that drug-drug interaction in vivo existed between PNS and ASA. The concentration of the SA was increasing when the two drugs were administered together. The transport of ASA and SA in MDCK -MDR1 cell monolayer was used to verify this conclusion. The values of apparent permeability coefficients (Papp) were significantly increased when the two drugs were used together. This result suggested PNS could increase the gastrointestinal tract absorption of ASA and SA. These findings provide more insight for wise use of two drugs to treat or prevent cardiovascular diseases.

In Situ and in Vivo Study of Nasal Absorption of Paeonol in Rats

The objective of this work was to study the in situ and in vivo nasal absorption of paeonol. A novel single pass in situ nasal perfusion technique was applied to examine the rate and extent of nasal absorption of paeonol by rats. Various experimental conditions, such as perfusion rate, pH, osmotic pressure and drug concentration, were investigated. The in situ experiments showed that the nasal absorption of paeonol was not dependent on drug concentration, and fitted a first order process. The absorption rate constant, Ka, increased with an increase in perfusion speed. Paeonol was better absorbed in acidic solutions than in neutral or alkaline solutions. The value of Ka was higher in a hypertonic environment than under isotonic or hypotonic conditions. In vivo studies of paeonol absorption were carried out in rats and the pharmacokinetics parameters of intranasal (i.n.) and intragastric (i.g.) administration were compared with intravenous (i.v.) administration. The bioavailabilities of paeonol were 52.37% and 15.81% for i.n. and i.g, respectively, while Tmax values were 3.05 ± 1.46 min and 6.30 ± 0.70 min. MRT (Mean Residence Time) were 23.19 ± 6.46 min, 41.49 ± 2.96 min and 23.09 ± 5.88 min for i.n., i.g. and i.v. methods, respectively. The results demonstrate that paeonol could be absorbed promptly and thoroughly by i.n. administration in rats.

Comparative pharmacokinetics of borneol in cerebral ischemia-reperfusion and sham-operated rats

Objective: This study was designed to investigate the pharmacokinetics of borneol in the pathological conditions of stroke and evaluate the pharmacokinetic differences of borneol caused by stroke after oral administration of borneol and Xingnaojing (XNJ). Methods: The rats were divided into two groups, ischemia-reperfusion (IR) and sham-operated (SO) rats. Each group contained two subgroups: pure borneol and XNJ subgroups. After administration with the same dosages of borneol 162.0 mg/kg, plasma samples were collected. The cerebral ischemia-reperfusion model was created by reversible middle cerebral artery occlusion (MCAO). The blood samples were collected punctually after oral administration and a specific gas chromatographic system-flame ionization detector (GC-FID) method was developed and employed to determine the level of borneol in the plasma. The pharmacokinetic parameters were analyzed using non-compartmental methods with Kinetica. Results: After administration of borneol, the maximum plasma concentration (Cmax) and area under the curve (AUC) values in stroke rats significantly increased by 302% and 275%, respectively, compared with the SO rats, and the same phenomenon appeared after administration of XNJ. In the rats with the same physiological conditions, the Cmax and AUC had higher values in the borneol subgroup (P<0.05). Conclusions: These results suggest that the pathological damages of ischemia-reperfusion have a significant impact on the pharmacokinetic traits of borneol and that there are some components in XNJ inhibiting the absorption of borneol.

Puerarin transport across a Calu-3 cell monolayer – an in vitro model of nasal mucosa permeability and the influence of paeoniflorin and menthol

Nasal administration is a high-potential delivery system, particularly because it can provide a pathway from the nose to the brain. The objective of this research is to characterize puerarin transport across a Calu-3 cell monolayer used as a model of the nasal mucosa and to evaluate the influence of puerarin in combination with paeoniflorin and menthol to explore the enhanced mechanism of the permeability at the cell level. The apparent permeability coefficients (Papp) of puerarin bidirectional transport were both <1.5×10−6 cm/s, and the efflux ratio was <1.5, indicating that puerarin alone exhibited poor absorption and that its transport primarily occurred by passive diffusion through the cell monolayer. When puerarin was coad ministered with paeoniflorin, the Papp was not changed (P>0.05). However, the addition of menthol significantly (P<0.05) improved the Papp of puerarin in both directions. Moreover, based on immunofluorescence experiments and transepithelial electrical resistance measurements, the data indicated that the drug compatibility opened tight junctions and weakened the barrier capabilities of epithelial cells, thereby promoting the permeability of puerarin.