Natural Borneol Research Articles

Effect of natural borneol on the pharmacokinetics and distribution of nimodipine in mice

The purpose of this study was to investigate the effect of natural borneol (NB) on the pharmacokinetics and distribution of nimodipine in mice. A single dose of nimodipine was administered intravenously (2 mg/kg) to mice pretreated with NB (250 mg/kg) or vehicle. Blood as well as brain, liver, and kidney tissue samples were collected at 5, 10, 20, 40, and 60 min post-dose nimodipine. The concentrations of nimodipine in plasma and tissues were determined by ultra performance liquid chromatography (UPLC) coupled with UV detection, and the pharmacokinetic parameters were calculated based on non-compartmental analysis. NB increased the plasma AUC5-60 min by 26 % compared to the vehicle. In addition, brain concentrations of nimodipine in NB-treated mice were significantly higher than those in control mice with the increased AUC5-60 min by 30 %. In liver and kidney, NB also caused 26 and 47 % increase in AUC5-60 min, respectively. These results implicated that NB may inhibit the metabolism or elimination of nimodipine and enhance its distribution in brain and kidney tissue.

Natural borneol enhances geniposide ophthalmic absorption in rabbits

The purpose of this study was to investigate the effects of natural borneol (NB) on the pharmacokinetics and bioavailability of ophthalmic administered geniposide (Ge) in rabbits. In vitro permeability characteristics of Ge in excised rabbit corneas were evaluated using Franz-type cells. The effect of NB on Ge pharmacokinetic profiles in vivo was studied with microdialysis. Concentrations of Ge were determined with reversed-phase high performance liquid chromatography (HPLC) following ophthalmic administration of Ge alone or with NB (0.01%, 0.02%, and 0.04%) or 0.5% ethylendiaminetetraacetic acid (EDTA). Ocular irritation was evaluated using the Draize method and histological examination. Ge solution alone (control solution) had limited corneal permeability. The ratio of the apparent permeability coefficient (Papp) with respect to the control solution significantly increased by approximately 1.6-, 2.0-, and 2.4-fold at NB concentrations of 0.01, 0.02, and 0.04%, respectively. The Papp for Ge with 0.5% EDTA (positive control) was approximately 1.7-fold higher than that for control solution. Compared to control solution, Ge exhibited a 1.46-, 2.16-, and 2.47-fold greater AUC0-6h, and 2.0-, 3.5-, and 4.4-fold greater Cmax, with 0.01, 0.02, and 0.04% NB, respectively, while Tmax remained unchanged. In conclusion, the ocular bioavailability of Ge significantly increased in the presence of NB.

Liquid Chromatography/Quadrupole Time-of-Flight Mass Spectrometry for Identification of In Vitro and In Vivo Metabolites of Bornyl Gallate in Rats

Bornyl gallate (BG) is a potential drug candidate synthesized by the reaction of two natural products, gallic acid and borneol. Previous studies have strongly suggested that BG is worthy of further investigation due to antioxidant, antiatherosclerosis activities, and obvious activity of stimulating intersegmental vessel growth in zebrafish. This work was designed to elucidate the metabolic profile of BG through analyzing its metabolites in vitro and in vivo by a chromatographic separation coupled with a mass spectrometry. The metabolites of BG were characterized from the rat liver microsome incubation solution, as well as rat urine and plasma after oral administration. Chromatographic separation was performed on an Agilent TC-C18 column (250 mm × 4.6 mm, 5 μm) with gradient elution using methanol and water containing 0.2% (V : V) formic acid as the mobile phase. Metabolites identification involved analyzing the retention behaviors, changes of molecular weights and MS/MS fragment patterns of BG and the metabolites. Five compounds were identified as isomers of hydroxylated BG metabolites in vitro. The major metabolites of BG in rat urine and plasma proved to be BG-O-glucuronide and O-methyl BG-O-glucuronide. The proposed method confirmed to be a reliable and sensitive alternative for characterizing metabolic pathways of BG.

Formation of β‐Cyclodextrin Inclusion Enhances the Stability and Aqueous Solubility of Natural Borneol

The aims of this study were to optimize the preparation conditions of natural borneol/β-cyclodextrin (NB/β-CD) inclusion complex by ultrasound method, and to investigate its improvement of stability and solubility. The complex was characterized by different various spectroscopic techniques including Fourier transform infrared spectroscopy, X-ray diffractometry, and differential scanning calorimetry. The results demonstrate that NB could be efficiently loaded into β-CD to form an inclusion complex by ultrasound method at a molar ratio of 1: 1and mass ratio of 1: 6. The complex exhibited different physicochemical characteristics from that of free NB. Typically, formation of β-CD inclusion significantly enhanced the stability and aqueous solubility of NB. Natural borneol (NB) has the potential to be widely used in the fields of medical and functional food, due to its specificity. However, the disadvantages of unstability in the preparation and storage process due to its easy sublimation and the low water solubility limit its application. This research provides an effective way to improve the solubility and stability of NB by preparing NB/β-CD inclusion complex. Furthermore, theoretical basis is also provided for the application development of NB.

Preparation of Natural Borneol/2-Hydroxypropyl-β-cyclodextrin Inclusion Complex and Its Effect on the Absorption of Tetramethylpyrazine Phosphate in Mouse

Natural borneol (NB)/2-hydroxypropyl-β-cyclodextrin (HP-β-CD) inclusion complex has been prepared, and characterized by differential scanning calorimetry (DSC), X-ray diffractometry (XRD) and Fourier transform infrared spectroscopy (FT-IR). The phase solubility and release of NB, and its effect on the absorption of tetramethylpyrazine phosphate (TMPP) in mice were also measured. The results demonstrated that NB could be efficiently loaded into HP-β-CD to form an inclusion complex at a mass ratio of 1 : 6, and the inclusion complex had different physicochemical characteristics from free NB. The profile of phase solubility displayed a typical A(L)-type, indicating the formation of 1 : 1 stoichiometric inclusion complex. Additionally, the stability of the inclusion complex was greatly improved compared with that of NB. The results of absorption of TMPP in mouse indicated that NB/HP-β-CD enhanced the absorption of TMPP and the concentration of TMPP in brain tissue, especially in the early period. Both TMPP plasma and brain concentration-time courses in mice were fitted to open two-compartment model with first-order absorption after oral administration of TMPP with NB/HP-β-CD. However, the use of NB/HP-β-CD did not change the in vivo behavior of TMPP. Our results suggest the application potential of NB/HP-β-CD inclusion in pharmaceutics.

Pharmacokinetics of natural borneol after oral administration in mice brain and its effect on excitation ratio

Previous studies have indicated that borneol has double side effects on the central nervous system (CNS), but the mechanism is unknown. The aim of this study was to clarify the relationship between excitation ratio [contents of excitatory amino acids (AAs) versus that of inhibitory] and the content of natural borneol after a single oral dose. Mice were administered a 1.2 g/kg dose of natural borneol (containing 98% D: -borneol) by oral ingestion. Brain samples were collected before administration and at 0.083, 0.167, 0.25, 0.333, 0.5, 0.75, 1, 1.5, 2, 2.5, 3, 4 and 5 h after administration. The brain concentration of natural borneol and contents of AA neurotransmitters in mice brain were determined by GC-MS and HPLC-FLU, respectively. After per oral application, natural borneol was absorbed rapidly into the brain and could be determined 5 min after dosing. The maximal brain concentration (86.52 μg/g) was reached after 1 h post-dosing. Natural borneol could affect the contents of AA neurotransmitters in mice brain: L: -aspartic acid increased significantly from 0.083 to 1 h after administration, L: -glutamic acid increased significantly at 0.333 h and decreased from 1.5 to 5 h, gamma-amino-N-butyric acid increased significantly from 0.167 to 5 h, whereas glycine was not affected. The excitation ratio is the contents of excitatory AAs versus that of inhibitory AAs, which reflects the excitatory or inhibitory state of the body. The excitation ratio elevated transitorily and then declined 0.5 h post-dosing; there were significant differences between 1.5-5 h post-dose compared with pre-dose. The present study indicated that natural borneol could affect the contents of AA neurotransmitters, and the change in excitatory ratio led to borneol's double side effects on the CNS.

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.

The in situ and in vivo study on enhancing effect of borneol in nasal absorption of Geniposide in rats

The objective of this research was to study the in situ and in vivo nasal absorption of Geniposide (Ge) co-administered with borneol. A rat in situ nasal perfusion technique with a novel volumeadjusted calculation was used to examine the absorption rate and extent of Ge. The influence of different experimental conditions such as purity of extract, drug concentration, co-administration with synthetic borneol or natural borneol were also investigated. Results indicated nasal absorption of Ge was primarily by passive diffusion that resembled first order kinetics. Following co-administration with borenol, the drug absorption was increased by 1.4 and 1.7 folds for natural borneol and synthetic borneol, respectively. However, the effect of other factors on drug absorption was not significant. In addition, it was also observed that there is a positive correlation between the absorption of water and Ge by the nasal route. In vivo studies carried out in rats where Ge was co-administered with NB and the pharmacokinetic profile obtained following intranasal administration were compared with those after intravenous administration. The bioavailability of Ge by intranasal was 101.5% and T(max) was 2.04 +/- 0.64 min. MRT was 218.7 +/- 74.1 min and 44.4 +/- 8.9 min for intranasal and intravenous, respectively. Combined with the borneol, Ge can be promptly and thoroughly absorbed intranasally in rats.

A Novel GC-MS Bioanalytical Method for Natural Borneol and Its Application in Investigating Natural Borneol Distribution in Mice

Abstract One of the major goals of our group is to understand the meridian tropism of natural borneol (NB). As a first step, this study served two purposes: to develop a GC-MS bioanalytical method for NB, and with the aid of this method to investigate NB distribution in mice. Mouse tissue samples, spiked with naphthalene as internal standard, were homogenated with NS and extracted using hexane. The extract supernatant was analyzed in GC-MS with conditions of DB-5MS capillary column (0.25mm×30m×0.25μm), electron impact (EI) ionization with energy of 70 eV and multiplier voltage of 1100 V, and Selected Ion Monitor (SIM, m/z 95 for camphor and NB, whereas m/z 128 for naphthalene) detection mode. The calibration curve was linear in the range from 22 ng/mL to 22 μg/mL with a regression equation Y= 0.000486X + 0.00036, R 2 =0.999 (n=3). The limit of detection was 10 ng/mL. The lower limit of quantitation was 22 ng/mL. The within-day and inter-day precisions were 3.72∼6.11% and 7.29∼17.6%, respectively. The relative recovery was 85.95∼107.93% and extraction recovery was 93.04∼103.03%. This bioanalytical method has sufficient recovery and is accurate and reliable for quantitating NB in tissues. The tissue distribution up to 150 min after a single oral dose of NB was investigated in mice. This compound was detected in most tissues. The liver had the highest concentration, followed by kidney, heart, brain, and others. Tissue concentration-time curves had double or triple peaks. The tissue distribution pattern suggested that NB may attribute to the cardio-system.

Influence of Borneol on In Vitro Corneal Permeability and on In Vivo and In Vitro Corneal Toxicity

This study examined whether borneol could enhance corneal drug permeability. Model drugs containing either synthetic or natural borneol were co-administered to isolated intact or de-epithelialized rabbit corneas and the apparent permeability coefficients were measured. Draize tests in rabbits and levels of isolated intact rabbit corneal hydration were used to measure in vivo and in vitro toxicity, respectively. Synthetic borneol (0.1%) increased corneal penetration of the lipophilic agents, indomethacin and dexamethasone, by 1.23 and 2.40, respectively, and of the hydrophilic agents, ofloxacin, ribavirin and tobramycin, by 1.87, 2.80 and 3.89, respectively. For natural borneol, the corresponding fold increases were 1.67, 2.00, 2.15, 2.18 and 3.39, respectively. Removing the epithelium attenuated the penetration-enhancing effects of borneol. Borneol (0.1%) did not damage corneal tissue. The ability of borneol to enhance drug penetration through the outer corneal layer, particularly for highly-hydrophilic drugs, suggests that further clinical investigation may be warranted.

Preliminary study: biotransformation of borneol to camphor in mice, rats, and rabbits

Abstract Objective This paper was to study the biotransformation of borneol to camphor in mice, rats, and rabbits. Methods Natural borneol was administered to the mice in a single oral dose of 1.0 g/kg. The mice were sacrificed 0.5 hr later. Plasma and liver samples were removed from the mice, and analyzed for both borneol and camphor using gas chromatography-mass spectrometry (GC-MS). The study was repeated with isoborneol and synthetic borneol. In a separate study, a suspension of natural borneol in 0.8%CMC-Na was administered to mice, rats, and rabbits. Blood samples were removed from the animals at different time points of postdosing, and analyzed for camphor using GC-MS. Results Study results showed that a mixture of borneol, isoborneol, and camphor were well separated by GC-MS method. Camphor was found in the plasma and liver of mice after administration of natural borneol, synthetic borneol, or isoborneol. Camphor concentration in the plasma was found to increase with time after oral administration of natural borneol to the mice, rats, and rabbits. Conclusion It is concluded that camphor appeared to be a common metabolite of natural borneol, synthetic borneol, and isoborneol in mice, rats, and rabbits.

Synthesis and crystal structure of a novel chiral compound prepared from (-)-borneol as a natural chiral auxiliary

The solid diastereoisomeric mixture4a+4b was obtained via the asymmetric Michael addition reaction of phenylthioalcohol with liquid epimeric mixture 5-(-)-bornyloxy-2(5H)-furanone3a+3b, which was prepared by reaction of the natural abundant chiral auxiliary borneol 2 with 5-hydroxy-2(5H)-furanone 1. The two diastereoisorners4a +4b were separated by means of preferential cyrstallization, which gave one optically pure compound4b with de > 98 %. The absolute configuration of4b was established by X-ray crystallography. The method provided a new efficient route for utilizing natural chiral auxiliaries and preparing optically pure diastereoisomeric compounds based on liquid epimers.