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DOI: 10.1055/s-0032-1328540
The Pharmacokinetics of Chelerythrine Solution and Chelerythrine Liposomes after Oral Administration to Rats
Correspondence
Publication History
received 12 November 2012
revised 27 January 2013
accepted 02 April 2013
Publication Date:
13 May 2013 (online)
Abstract
Chelerythrine is a quaternary benzo[c]phenanthridine alkaloid which has many potent pharmacological effects and can dissolve well in water; dihydrochelerythrine has recently been identified as a chelerythrine metabolite in rat. Most methods of preparation of liposomes suffer from the drawback of poor incorporation of water-soluble drugs. The emulsion/solvent evaporation method is a relatively simple and efficient way to prepare liposomes loaded with hydrophilic drugs. The aim of this study was therefore to find a suitable formulation to enhance the incorporation of chelerythrine into liposomes by the emulsion/solvent evaporation method and so improve the therapeutic efficacy of chelerythrine. Results showed that the chelerythrine-liposome has been successfully prepared by the emulsion/solvent evaporation method: the entrapment efficiency of chelerythrine was higher at 78.6 %, and the drug loadings reached 7.8 %. The relative bioavailability of chelerythrine and its dihydro derivative in liposomes was significantly increased compared with that of the chelerythrine solution. The area under the plasma concentration–time curve values of chelerythrine and dihydrochelerythrine after oral administration of chelerythrine-liposomes were 4.83-fold and 2.02 higher than those obtained with the chelerythrine solution. The half time and peak concentrations of chelerythrine and dihydrochelerythrine were also higher for chelerythrine-liposomes than that for chelerythrine. In contrast, the total body clearance and apparent volume of distribution were lower for chelerythrine-liposomes in comparison to the respective parameters for the chelerythrine solution. It can thus be concluded that incorporation into liposomes prolonged chelerythrine retention within the systemic circulation.
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Abbreviations
CHE: chelerythrine
DHCHE: dihydrochelerythrine
LPs: liposomes
EE%: entrapment efficiency
DL%: drug loading
Ke: the elimination rate constant
AUC: area under the plasma concentration–time curve
t 1/2: half time
C max: peak concentration
CL: total body clearance
V/f(c) : apparent volume of distribution
SG: sanguinarine
TCM: traditional Chinese medicines
IS: internal standard
PDI: polydispersity index
CMC: carboxymethyl cellulose
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Introduction
CHE and SG are quaternary benzo[c]phenanthridine alkaloids which are widely distributed in the Papaveraceae and Rutaceae families of plants, which are often TCM, such as the greater celandine herb (known as Baiqucai in China), officially listed in the Chinese Pharmacopoeia (2010) [1]. CHE and SG have been shown to primarily display anti-tumor, anti-microbial and anti- inflammatory properties [2]. CHE is a bioactive compound that also possesses those bioactivities [3]. In the Chinese Pharmacopoeia, CHE is recommended as a marker compound for identification of Baiqucai. Recently, some studies showed that the benzo[c]phenanthridine alkaloid can undergo reduction leading to the formation of non-charged dihydro metabolites in the tissues and body fluids of living organisms [4], [5]. In vivo studies have shown that DHSG was identified as SG metabolite by high-performance liquid chromatography-electrospray ionization mass spectrometry; however, the expected benz[c]acridine was not found in rat plasma by many researchers nor were other compounds [5], [6], [7]. The conversion of SG to less toxic DHSG was likely the elimination pathway of SG in mammals [4].
LPs are on the same size scale as receptors, channels, ligands, effectors, and nucleic acids [8]. Many clinical results suggest that LP-based therapeutics can show enhanced efficacy, while also reducing side effects, due to properties such as more targeted localization in tumors and active cellular uptake [9]. LPs are a spherical, self-closed formed lipid bilayer, in which the encapsulated drugs and radionuclides rely on pH or chemical gradients crossing the bilayer membrane [10]. In recent years, LPs have attracted much attention as drug delivery systems and are particularly suitable tools for the present investigation. Due to their unique size-dependent properties, LPs hold great promise for reaching the goal of controlled and site-specific drug delivery and can improve the pharmacokinetic and therapeutic properties of anticancer drugs [11]. Methods universally used in preparing LPs include high-pressure homogenization, high-shear homogenization and ultrasound, emulsion solvent/evaporation, solvent injection and micro emulsion, and others [12]. Among the present encapsulation techniques, the emulsion/solvent evaporation method is a relatively simple and efficient way to prepare LPs loaded with hydrophilic drugs [11]. In the modified emulsion/solvent evaporation method, lipophilic material is dissolved in an organic solvent emulsified in an aqueous phase to give an oil/water (o/w) emulsion. After evaporation of the organic solvent, the emulsion is poured into cold water, and LPs are formed.
Pharmacokinetics, sometimes described as what the body does to a drug, refers to the movement of drug into, through, and out of the body – the time course of its absorption, bioavailability, distribution, metabolism, and excretion. Pharmacokinetic studies of the active ingredients in TCM will improve our ability to explain their mechanisms of action and help to promote the development of this medical practice [13]. Nowadays, CHE are analytes of much interest. There are over 4700 papers on CHE listed on Chemical Abstracts. However, there is a limited number of reports on the analysis of CHE having to do with LC (liquid chromatography in vivo), and as far as we are aware, there is no report of the determination of CHE in vivo. CHE and DHCHE can be separated well using HPLC at the same wavelength. In this study we developed and validated a rapid, sensitive, and accurate HPLC method for determination of CHE and its metabolite in rat plasma after oral administration so as to obtain an overview of its pharmacokinetic profile. In addition, CHE was prepared to LPs by the emulsion/solvent evaporation method, and the pharmacokinetic profiles of CHE-LPs and CHE in rats were compared.
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Material and Methods
Chemicals and reagents
CHE (98 % pure, [Fig. 1 A]) was purchased from Xiʼan Honson Biotechnology Co., Ltd. and identified by the Pharmacognosy Laboratory, School of Medicine, Xiʼan Jiaotong University (Xiʼan, China). Berberine (98 % pure, [Fig. 1 B]), used as IS, and DHCHE (98 % pure, [Fig. 1 C]) were purchased from the National Institute for the Control of Pharmaceutical and Biological Products (Beijing, China). Glycerin monostearate was purchased from Shanghai Chemical Reagent Co., Ltd. Lecithin was purchased from Tianjin Rui Mingwei Chemical Co., Ltd. Poloxamer F-127 was purchased from Shenzhen YoupuHui Company. PEG 400 was purchased from Sigma, dehydrated alcohol from Jinan Huifengda Chemical Co., Ltd., and Sephadex G-50 from Pharmacia. Methanol, acetonitrile, and phosphoric acid for HPLC were purchased from Merck. All other reagents were of analytical grade. Double-distilled water was used throughout the study.


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Preparation of CHE-LPs
Various techniques have been used to manufacture nanosized drug particles with size down to hundreds and even tens of nanometers. One of the popular methods for the encapsulation of drug is the emulsion/solvent evaporation method [11]. The CHE-LPs were prepared according to a modified emulsion solvent evaporation [14]. In brief, 10 mg CHE, 40 mg lecithin, and 100 mg glycerin monostearate were dissolved in 10 mL dehydrated ethanol (organic phase) at 75 °C. 30 mL aqueous phase (1 % Poloxamer-127 containing 1 % PEG 400, w/v) was heated to the same temperature of the organic phase. Then the organic phase was injected into the hot aqueous phase under rapid stirring at 1200 rpm for dispersion. After that the homogeneous suspension was dispersed in water (ratio of suspension to water, 1 : 1 v/v) under stirring at 1000 rpm for 4 h at 2 °C in an ice bath to allow for the hardening of the LPs. The resulting suspension was filtered through a membrane with 0.45 µm pore size.
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Characterization of particles
Size and morphology: The morphology of the particles, particle size, zeta potential and PDI were determined using Zetasizer 3000 HS (Malvern Instruments Ltd.) based on quasi-elastic light scattering. Size measurements were performed in triplicate following a proper dilution of the nanoparticles suspension in distilled water at 25 °C.
Encapsulation efficiency and drug loading: EE% of CHE-LPs was determined after separating free drugs from LPs by a Sephadex G-50 chromatography. 1.0 mL CHE-LPs suspension was added to the top of the Sephadex-G50 column and washed with distilled water at a flow rate of 2.0 mL/min [15], [16]. The collected samples were metered with methanol to 50 mL, filtered through a 0.45 µm membrane, and then measured using HPLC. All experiments were performed in triplicate, and EE% was calculated according to the following equation:
EE% = (WT − WF)/WT × 100 %
DL% = (WT − WF)/WC × 100 %
WT: Total quantity of incorporated and non-incorporated CHE in the LPs; WF: free drug separated with gel chromatography; WC: total carrier material.
In vitro release study: The in vitro release profile of CHE-LPs was determined according to the dialysis bag method [17]. The dialysis bag has a molecular weight cut-off of 14 000 and was soaked in double-distilled water for 12 h before use. 20 mL of CHE-LP dispersion (1 mg/mL) was transferred to the bag which was placed in a thermostatic shaker at 37 ± 1 °C and 100 strokes/min. The release of CHE from solution in PH7.4 PBS (0.5 M) containing 1 % methanol (as a control) through the dialysis bag was also studied using the same medium. Samples were withdrawn at predetermined time intervals, and the same volume of fresh dissolution medium was replaced. The CHE content of the filtrate was determined by HPLC. All experiments were repeated 3 times, and the average values were taken.
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Animals
Male Wistar rats (200–220 g) were purchased from the Experimental Animal Center of the Xiʼan Jiaotong University (Xiʼan, China). They were housed and cared for under standard conditions for 3 days before starting the experiments, then fed with food and water ad libitum and fasted overnight before drug administration. All experimental procedures utilizing rats were in accordance with the guidelines approved by the Institutional Animal Care and Ethical Committee of the Xiʼan Jiaotong University. (Number: 165, Xiʼan, China, 13/5/2012).
0.6 mL blood samples were taken from the terminal retro-orbital bleeding before (0 h) and 0.083, 0.17, 0.25, 0.33, 0.5, 1.0, 1.5, 2.0, 4.0, 6.0, 8.0 12.0, and 24.0 h after dosing, then immediately transferred to heparinized tubes and centrifuged at 10 000 g for 10 min. The plasma obtained was stored frozen at − 20 °C until analysis.
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Pharmacokinetic evaluation
Pharmacokinetic studies were performed as described elsewhere [22]. Rats were randomly divided into two groups (6 per group). Group 1 was treated with CHE solution, whilst group 2 was treated with the CHE-LPs solution. CHE was dissolved in 1 % CMC by ultrasonic processing in ultrasonic cleaner (SB5200DTD) to obtain a CHE solution with concentration of 2 mg/mL; the CHE-LPs were diluted in 5 % glucose aqueous solution to obtain the same concentration. Each preparation was orally administered to rats at the CHE dose of 10 mg/kg.
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Data analysis
The plasma concentrations of CHE and DHCHE at different times were expressed as mean ± SD, and the mean concentration-time curve was plotted. SPSS version 15.0 was used for all statistical analyses. C max and T max were derived directly from the experimental points. The other pharmacokinetical parameters were computed using 3p97 software supplied by the Pharmacological Society of China (Beijing, China).
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Supporting information
The experiments and results of the chromatographic system, stock solutions preparation, calibration plot and quality-control samples preparation, as well as sample preparation and bioanalytical method validation are shown in the Supporting Information (see [Tables 1], [2] and [3]).
Nominal concentration (µg/mL) |
Intra-day |
Inter-day |
||||
---|---|---|---|---|---|---|
Measured concentration (mean ± SD) |
Accuracy (%) |
RSD (%) |
Measured concentration (mean ± SD) |
Accuracy (%) |
RSD (%) |
|
0.1 |
0.094 ± 0.008 |
94.0 |
8.51 |
0.092 ± 0.009 |
92.0 |
9.78 |
5.0 |
4.985 ± 0.098 |
99.7 |
1.97 |
4.887 ± 0.065 |
97.7 |
1.33 |
15.0 |
14.962 ± 0.166 |
99.7 |
1.11 |
15.142 ± 0.141 |
100.9 |
0.93 |
Nominal concentration (µg/mL) |
Intra-day |
Inter-day |
||||
---|---|---|---|---|---|---|
Measured concentration (mean ± SD) |
Accuracy (%) |
RSD (%) |
Measured concentration (mean ± SD) |
Accuracy (%) |
RSD (%) |
|
0.05 |
0.047 ± 0.002 |
94.0 |
4.26 |
0.048 ± 0.004 |
96.0 |
8.33 |
0.5 |
0.474 ± 0.022 |
94.8 |
4.45 |
0.511 ± 0.039 |
102.2 |
7.63 |
5.0 |
4.889 ± 0.053 |
97.8 |
1.08 |
4.987 ± 0.085 |
99.7 |
1.70 |
Conditions |
Nominal concentration (µg/mL) |
CHE |
DHCHE |
||
---|---|---|---|---|---|
Measured concentration (mean ± SD) |
Accuracy (%) |
Measured concentration (mean ± SD) |
Accuracy (%) |
||
Short-term stability |
0.1 |
0.096 ± 0.004 |
96.0 |
0.093 ± 0.004 |
93.0 |
5.0 |
4.933 ± 0.014 |
98.6 |
4.876 ± 0.014 |
97.5 |
|
15.0 |
14.424 ± 0.355 |
96.2 |
14.844 ± 0.355 |
99.0 |
|
Stability after 3 freeze/thaw cycles |
0.1 |
0.093 ± 0.014 |
93.0 |
0.093 ± 0.006 |
93.0 |
5.0 |
4.897 ± 0.312 |
97.9 |
4.912 ± 0.014 |
98.2 |
|
15.0 |
14.893 ± 0.276 |
99.3 |
14.634 ± 0.198 |
97.6 |
|
Stability in storage (− 20 °C, 30 days) |
0.1 |
0.091 ± 0.005 |
91.0 |
0.088 ± 0.003 |
88.0 |
5.0 |
4.981 ± 0.145 |
99.6 |
4.796 ± 0.036 |
95.9 |
|
15.0 |
15.137 ± 0.434 |
100.9 |
14.765 ± 0.314 |
98.4 |
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Results and Discussion
According to our preliminary experiments, through single factor study, we found that the ratio of lecithin: glycerin monostearate: CHE, organic: aqueous phase, as well as the kind of emulsifier and dosage had significant effects on the stability and EE% of LPs. Through orthogonal experimental design, we came to an optimized recipe of CHE-LPs that is as follows, lecithin : glycerin monostearate 1 : 2.5, organic phase : aqueous phase 1 : 3, mixture of Poloxamer-127 and PEG 400 (1 % Poloxamer-127 containing 1 % PEG 400, w/v), CHE 10 mg.
It is generally acknowledged that liposome size influences the in vitro characteristics of nanocarriers such as drug loading capacity, aggregation, and sedimentation. The pharmacokinetic behavior, including blood circulation time, fusion adsorption on target cell membrane, and contact release of the carrier, is also strongly size-dependent [19]. A proper dilution of LPs showed that CHE-LPs particles had subsphaeroidal and uniform shapes, and the morphology of the LPs indicated that CHE-LPs were successfully obtained by the above method. The single factor study showed that the mean diameter was 112.8 ± 0.3 nm ([Fig. 2]) with the use of the optimized recipe for CHE-LPs, and under these conditions, the LPs had a zeta potential of − 12.3 ± 0.9 mV. As LPs are usually polydisperse in nature, measurement of PDI is important to know the size distribution of the nanoparticles. Most of the researchers accept a PDI value less than 0.3 as optimum value [20], [21]. Our research results indicated that the PDI was 0.338 ± 0.023, which was close to the optimum value.


The EE%, which is a measure of the percentage of the total compound entrapped within the LPs, is an important index to characterize drug delivery systems. A high EE% would be beneficial in incorporating the required dose in the minimum volume, facilitating local administration. In this study, we found that not only particle size had an effect on EE%, but also the types of solvent and emulsifier could influence the EE%. The orthogonal test showed that ethanol accompanied with Poloxamer-127 and PEG had higher EE%, which reached 78.6 %, and the batch-to-batch reproducibility of the EE% presented standard deviations of 3.2 %. It was also found that the solvents and their combinations had no significant effect on the DL%, which did not support a possible role of organic solvents on CHE entrapment under the studied conditions. However, in our preliminary study, we found that the phospholipid/CHE ratio and the kind of carrier had pronounced effect on the DL%. It seemed that interactions between CHE and Poloxamer-127 and PEG, together with the phospholipid/CHE ratio we chose above, were substantial for achieving a high DL% which reached 7.8 % and consequently led to the high EE% of CHE-LPs.
An important point to consider when studying design is the LPs capability to withstand passage through the blood for the oral administration of CHE-LPs. It might be assumed that the in vitro drug release should be assessed ideally in a medium which can better simulate the acidic condition of the gastrointestinal fluid. The pH effects on the drug release from the nanoparticles have been well investigated, and it was found that the acidic condition would speed the drug release in general. Nevertheless, this is not an important issue since the CHE would stay within the gastro-intestinal track for a few hours only. Drug release in plasma plays a more important role, so the pH 7.4 PBS was chosen. In vitro release has been used as a very important surrogate indicator of in vivo performance. [Fig. 3] describes the drug release profiles of CHE-LPs and CHE solutions. It can be seen that the release rate of the CHE solution was faster than that of CHE-LPs, and this indicated that LPs dispersion showed a retarded release of the drug from the lipid matrix when compared with the plain CHE solution. The CHE-LPs release profile showed a biphasic behavior. Excluding the burst effect in the early time data points (time points up to 1 hour), no significant burst effect was observed later. The initial in vitro burst release is probably caused by the drug adsorbed on the nanoparticles surface or precipitated from the superficial lipid matrix [23]. The sustained release is probably due to sustained drug release from the lipid matrix and is assumed to be controlled by the diffusion rate of the drug across the liposomal bilayer.


The analytical method was applied successfully in a pharmacokinetics study of CHE-LPs and CHE in rat plasma after oral administration. [Fig. 4] shows chromatograms of CHE, DHCHE, and IS in plasma samples. Typical retention times of CHE, DHCHE, and IS were 7.02, 14.15, and 4.12 min, respectively. DHCHE is apparently the primary metabolite of CHE as shown in [Fig. 5] compared with [Fig. 4]. Plasma pharmacokinetic parameters of CHE-LPs formulations were compared to those of CHE solution formulation. The mean plasma concentration-time curve profiles of the CHE solution and CHE-LPs are illustrated in [Figs. 6] and [7]. The pharmacokinetic parameters and the compartment model were analyzed by software program 3p97. The relevant pharmacokinetic parameters are listed in [Tables 4] and [5]. From [Fig. 6] and [Table 4], it can be seen that the plasma level of CHE and DHCHE was detectable up to approximately 24 or 12 h after administration of CHE-LPs. The likely profile and data of CHE and DHCHE after administration of the CHE solution were shown in [Fig. 7] and [Table 5]. The AUC was about 4.47-fold higher for CHE-LPs (ca. 30.78 µg/mL×h) compared to CHE (ca. 6.89 µg/mL×h). Similarly, the primary metabolite DHCHE of CHE-LPs was about 1.88-fold higher than that of CHE solution. t1/2 of CHE-LPs (ca. 5.66 h) was longer than that of CHE (ca. 0.23 h). Cmax values of CHE and DHCHE were also higher for CHE-LPs than that for CHE. Conversely, the volume of distribution of CHE-LPs was 2.13 (mg/kg)/(µg/mL), and this was considerably smaller than that of the CHE solution with 5.32 (mg/kg)/(µg/mL). In addition, CHE had a much larger CL as compared to CHE-LPs, possibly due to the fact that the CHE solution had a larger volume of distribution than CHE-LPs, while DHCHE always had the same tendency as CHE in CHE-LPs and CHE solution. For these results, we can conclude that the absorption of CHE and its metabolite DHCHE was enhanced significantly by employing LPs compared with a CHE solution.








Parameters |
Unit |
CHE |
DHCHE |
---|---|---|---|
Ke |
1/h |
0.12 ± 0.01 |
1.66 ± 0.09 |
t 1/2 |
h |
5.66 ± 0.19 |
1.41 ± 0.01 |
T (max) |
h |
1.23 ± 0.12 |
1.15 ± 0.15 |
C (max) |
µg/mL |
2.38 ± 0.33 |
1.23 ± 0.22 |
AUC |
(µg/mL) × h |
30.78 ± 1.12 |
8.13 ± 0.44 |
CLs |
mg/kg/h/(µg/mL) |
0.52 ± 0.11 |
0.84 ± 0.08 |
V/ f(c) |
(mg/kg)/(µg/mL) |
2.13 ± 0.32 |
3.82 ± 0.27 |
Parameters |
Unit |
CHE |
DHCHE |
---|---|---|---|
Ke |
1/h |
5.33 ± 0.31 |
6.43 ± 0.85 |
t 1/2 |
h |
0.23 ± 0.07 |
0.11 ± 0.03 |
T max |
h |
0.43 ± 0.02 |
0.39 ± 0.04 |
Cmax |
µg/mL |
1.47 ± 0.26 |
0.95 ± 0.02 |
AUC |
(µg/mL) × h |
6.89 ± 0.92 |
4.32 ± 0.21 |
CL |
mg/kg/h/(µg/mL) |
1.37 ± 0.17 |
1.69 ± 0.17 |
V/f(c) |
(mg/kg)/(µg/mL) |
5.32 ± 0.88 |
5.69 ± 0.47 |
In conclusion, CHE-LPs have been successfully prepared by the emulsion/solvent evaporation method; their encapsulation efficiency in this study was satisfactory at 78 % and narrow particle size dispersion. Previous studies have shown that when the HPLC-mass spectrometry method is used in the examination of CHE and SG metabolites, just the presence of DHCHE or DHSG can be determined. Compared to the previous study, the metabolite DHCHE can be examined and separated with CHE and IS berberine by present HPLC method. A new HPLC method with liquid–liquid extraction and UV detection has been developed and validated for determination of CHE in rat plasma after oral administration of a CHE solution and CHE-LPs. The method was found to be rapid, linear, accurate, and reproducible and proved suitable for pharmacokinetic investigations in rats after oral administration of CHE solution and CHE-LPs; it meets the current requirements for bioanalytical methods as specified by the Pharmacopoeia Committee of China [17]. However, the CHE was not significantly metabolized into DHCHE after oral administration of CHE compared with the previous in vivo studies of SG [5]. LPs encapsulation was found to change the in vivo disposition of CHE after oral administration into rats. CHE-LPs enabled a markedly longer residence time in the systemic circulation than the CHE solution.
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Conflict of Interest
The authors report no conflict of interest.
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References
- 1 The pharmacopoeia of the peopleʼs Republic of China. Part II. Beijing: The Pharmacopoeia Commission of PRC; 2010
- 2 Mazzanti G, Di Sotto A, Franchitto A, Mammola CL, Mariani P, Mastrangelo S, Menniti-Ippolito F, Vitalone A. Chelidonium majus is not hepatotoxic in Wistar rats, in a 4 weeks feeding experiment. J Ethnopharmacol 2009; 126: 518-524
- 3 Niu XF, Zhou P, Li WF, Xu HB. Effects of chelerythrine, a specific inhibitor of cyclooxygenase-2, on acute inflammation in mice. Fitoterapia 2011; 82: 620-625
- 4 Kosina P, Vacek J, Papoušková B, Stiborová M, Stýskala J, Cankař P, Vrublová E, Vostálová J, Simánek V, Ulrichová J. Identification of benzo[c]phenanthridine metabolites in human hepatocytes by liquid chromatography with electrospray ion-trap and quadrupole time-of-flight mass spectrometry. J Chromatogr B Analyt Technol Biomed Life Sci 2011; 879: 1077-1085
- 5 Vecera R, Klejdus B, Kosina P, Orolin J, Stiborová M, Smrcek S, Vicar J, Dvorák Z, Ulrichová J, Kubán V, Anzenbacher P, Simánek V. Disposition of sanguinarine in the rat. Xenobiotica 2007; 37: 549-558
- 6 Vacek J, Vrublová E, Kubala M, Janovská M, Fojta M, Šimková E, Stýskala J, Skopalová J, Hrbáč J, Ulrichová J. Oxidation of sanguinarine and its dihydro-derivative at a pyrolytic graphite electrode using Ex Situ Voltammetry. Study of the interactions of the alkaloids with DNA. Electroanalysis 2011; 23: 1671-1680
- 7 Vrublova E, Vostalova J, Vecera R, Klejdus B, Stejskal D, Kosina P, Zdarilova A, Svobodova A, Lichnovsky V, Anzenbacher P, Dvorak Z, Vicar J, Simanek V, Ulrichova J. The toxicity and pharmacokinetics of dihydrosanguinarine in rat: A pilot study. Food Chem Toxicol 2008; 46: 2546-2553
- 8 Pison U, Welte T, Giersig DA, Groneberg M. Nanomedicine for respiratory diseases. Eur J Pharmacol 2006; 533: 341-350
- 9 Torchilin VP. Recent advances with liposomes as pharmaceutical carriers. Nat Rev Drug Discov 2005; 4: 145-160
- 10 Chen LC, Wu YH, Liu IH, Ho CL, Lee WC, Chang CH, Lan KL, Ting G, Lee TW, Shien JH. Pharmacokinetics, dosimetry and comparative efficacy of (188)Re-liposome and 5-FU in a CT26-luc lung-metastatic mice model. Nucl Med Biol 2012; 39: 35-43
- 11 Mukherjee S, Ray S, Thakur RS. Solid lipid nanoparticles: a modern formulation approach in drug delivery system. Indian J Pharm Sci 2009; 71: 349-358
- 12 Mehnert W, Mader K. Solid lipid nanoparticles: production, characterization and applications. Adv Drug Deliv Rev 2001; 47: 165-196
- 13 Li Q, Jia Y, Sun LX, Xu L, Tong L, Shen ZD, Liu YL, Bi KS. High-performance liquid chromatographic determination of isofraxidin in rat plasma. Chromatographia 2006; 63: 249-253
- 14 Liu DF, Jiang SM, Shen H, Qin S, Liu JJ, Zhang Q, Li R, Xu QW. Diclofenac sodium-loaded solid lipid nanoparticles prepared by emulsion/solvent evaporation method. J Nanopart Res 2011; 13: 2375-2386
- 15 Reddy LH, Vivek K, Bakshi N, Murthy RS. Tamoxifen citrate loaded solid lipid nanoparticles (SLN): preparation, characterization, in vitro drug release, and pharmacokinetic evaluation. Pharm Dev Technol 2006; 11: 167-177
- 16 Liu J, Hu W, Chen H, Ni Q, Xu H, Yang X. Isotretinoin-loaded solid lipid nanoparticles with skin targeting for topical delivery. Int J Pharm 2007; 328: 191-195
- 17 Zhang X, Lu S, Han J, Sun S, Wang L, Li Y. Preparation, characterization and in vivo distribution of solid lipid nanoparticles loaded with syringopicroside. Pharmazie 2011; 66: 404-407
- 18 China SFDA. Technical guideline on non-clinical pharmacokinetic studies, 2005. Available at. http://www.sfda.com Accessed 2012
- 19 Gao SH, Fan GR, Hong ZY, Yin XP, Yang SL, Wu YT. HPLC determination of polydatin in rat biological matrices: application to pharmacokinetic studies. J Pharm Biomed Anal 2006; 41: 240-245
- 20 Suresh G, Manjunath K, Venkateswarlu V, Satyanarayana V. Preparation, characterization, and in vitro and in vivo evaluation of lovastatin solid lipid nanoparticles. AAPS Pharm Sci Technol 2007; 8: 162-170
- 21 Zhang J, Fan Y, Smith E. Experimental design for the optimization of lipid nanoparticles. J Pharm Sci 2009; 98: 1813-1819
- 22 Anton N, Benoit JP, Saulnier P. Design and production of nanoparticles formulated from nano-emulsion templates-a review. J Control Release 2008; 128: 185-199
- 23 Das S, Chaudhury A. Recent advances in lipid nanoparticle formulations with solid matrix for oral drug delivery. AAPS Pharm Sci Technol 2011; 12: 62-76
Correspondence
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References
- 1 The pharmacopoeia of the peopleʼs Republic of China. Part II. Beijing: The Pharmacopoeia Commission of PRC; 2010
- 2 Mazzanti G, Di Sotto A, Franchitto A, Mammola CL, Mariani P, Mastrangelo S, Menniti-Ippolito F, Vitalone A. Chelidonium majus is not hepatotoxic in Wistar rats, in a 4 weeks feeding experiment. J Ethnopharmacol 2009; 126: 518-524
- 3 Niu XF, Zhou P, Li WF, Xu HB. Effects of chelerythrine, a specific inhibitor of cyclooxygenase-2, on acute inflammation in mice. Fitoterapia 2011; 82: 620-625
- 4 Kosina P, Vacek J, Papoušková B, Stiborová M, Stýskala J, Cankař P, Vrublová E, Vostálová J, Simánek V, Ulrichová J. Identification of benzo[c]phenanthridine metabolites in human hepatocytes by liquid chromatography with electrospray ion-trap and quadrupole time-of-flight mass spectrometry. J Chromatogr B Analyt Technol Biomed Life Sci 2011; 879: 1077-1085
- 5 Vecera R, Klejdus B, Kosina P, Orolin J, Stiborová M, Smrcek S, Vicar J, Dvorák Z, Ulrichová J, Kubán V, Anzenbacher P, Simánek V. Disposition of sanguinarine in the rat. Xenobiotica 2007; 37: 549-558
- 6 Vacek J, Vrublová E, Kubala M, Janovská M, Fojta M, Šimková E, Stýskala J, Skopalová J, Hrbáč J, Ulrichová J. Oxidation of sanguinarine and its dihydro-derivative at a pyrolytic graphite electrode using Ex Situ Voltammetry. Study of the interactions of the alkaloids with DNA. Electroanalysis 2011; 23: 1671-1680
- 7 Vrublova E, Vostalova J, Vecera R, Klejdus B, Stejskal D, Kosina P, Zdarilova A, Svobodova A, Lichnovsky V, Anzenbacher P, Dvorak Z, Vicar J, Simanek V, Ulrichova J. The toxicity and pharmacokinetics of dihydrosanguinarine in rat: A pilot study. Food Chem Toxicol 2008; 46: 2546-2553
- 8 Pison U, Welte T, Giersig DA, Groneberg M. Nanomedicine for respiratory diseases. Eur J Pharmacol 2006; 533: 341-350
- 9 Torchilin VP. Recent advances with liposomes as pharmaceutical carriers. Nat Rev Drug Discov 2005; 4: 145-160
- 10 Chen LC, Wu YH, Liu IH, Ho CL, Lee WC, Chang CH, Lan KL, Ting G, Lee TW, Shien JH. Pharmacokinetics, dosimetry and comparative efficacy of (188)Re-liposome and 5-FU in a CT26-luc lung-metastatic mice model. Nucl Med Biol 2012; 39: 35-43
- 11 Mukherjee S, Ray S, Thakur RS. Solid lipid nanoparticles: a modern formulation approach in drug delivery system. Indian J Pharm Sci 2009; 71: 349-358
- 12 Mehnert W, Mader K. Solid lipid nanoparticles: production, characterization and applications. Adv Drug Deliv Rev 2001; 47: 165-196
- 13 Li Q, Jia Y, Sun LX, Xu L, Tong L, Shen ZD, Liu YL, Bi KS. High-performance liquid chromatographic determination of isofraxidin in rat plasma. Chromatographia 2006; 63: 249-253
- 14 Liu DF, Jiang SM, Shen H, Qin S, Liu JJ, Zhang Q, Li R, Xu QW. Diclofenac sodium-loaded solid lipid nanoparticles prepared by emulsion/solvent evaporation method. J Nanopart Res 2011; 13: 2375-2386
- 15 Reddy LH, Vivek K, Bakshi N, Murthy RS. Tamoxifen citrate loaded solid lipid nanoparticles (SLN): preparation, characterization, in vitro drug release, and pharmacokinetic evaluation. Pharm Dev Technol 2006; 11: 167-177
- 16 Liu J, Hu W, Chen H, Ni Q, Xu H, Yang X. Isotretinoin-loaded solid lipid nanoparticles with skin targeting for topical delivery. Int J Pharm 2007; 328: 191-195
- 17 Zhang X, Lu S, Han J, Sun S, Wang L, Li Y. Preparation, characterization and in vivo distribution of solid lipid nanoparticles loaded with syringopicroside. Pharmazie 2011; 66: 404-407
- 18 China SFDA. Technical guideline on non-clinical pharmacokinetic studies, 2005. Available at. http://www.sfda.com Accessed 2012
- 19 Gao SH, Fan GR, Hong ZY, Yin XP, Yang SL, Wu YT. HPLC determination of polydatin in rat biological matrices: application to pharmacokinetic studies. J Pharm Biomed Anal 2006; 41: 240-245
- 20 Suresh G, Manjunath K, Venkateswarlu V, Satyanarayana V. Preparation, characterization, and in vitro and in vivo evaluation of lovastatin solid lipid nanoparticles. AAPS Pharm Sci Technol 2007; 8: 162-170
- 21 Zhang J, Fan Y, Smith E. Experimental design for the optimization of lipid nanoparticles. J Pharm Sci 2009; 98: 1813-1819
- 22 Anton N, Benoit JP, Saulnier P. Design and production of nanoparticles formulated from nano-emulsion templates-a review. J Control Release 2008; 128: 185-199
- 23 Das S, Chaudhury A. Recent advances in lipid nanoparticle formulations with solid matrix for oral drug delivery. AAPS Pharm Sci Technol 2011; 12: 62-76













