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Zhibin Wang Key Laboratory of Basic and Application Research of Beiyao (Heilongjiang University of Chinese Medicine), Ministry of Education, 24 Heping Road, Xiangfang District, Harbin 150040, China

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Yaodan Chang Key Laboratory of Basic and Application Research of Beiyao (Heilongjiang University of Chinese Medicine), Ministry of Education, 24 Heping Road, Xiangfang District, Harbin 150040, China

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Feng Cao Key Laboratory of Basic and Application Research of Beiyao (Heilongjiang University of Chinese Medicine), Ministry of Education, 24 Heping Road, Xiangfang District, Harbin 150040, China

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Chunjuan Yang Harbin Medical University, College of Pharmacy, 157 Baojian Road, Nangang District, Harbin 150040, China

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Zhenyue Wang Key Laboratory of Basic and Application Research of Beiyao (Heilongjiang University of Chinese Medicine), Ministry of Education, 24 Heping Road, Xiangfang District, Harbin 150040, China

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Haixue Kuang Key Laboratory of Basic and Application Research of Beiyao (Heilongjiang University of Chinese Medicine), Ministry of Education, 24 Heping Road, Xiangfang District, Harbin 150040, China

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Abstract

A rapid and simple ultra-performance liquid chromatography-electrospray ionization-tandem mass spectrometry (UPLC-ESI-MS/MS) method was developed and validated for simultaneous determination of six analytes from the Eleutherococcus senticosus (Rupr. & Maxim.) Maxim. leaves (ESL) in beagle dog plasma for the first time, including 3-O-α-l-rhamnopyranosyl-(1→2)-α-l-arabinopyranoside-29-hydroxy oleanolic acid, 3-O-β-d-glucopyranosyl-(1→2)-α-l-arabinopyranoside-29-hydroxy oleanolic acid, 3-O-β-d-glucopyranosyl-(1→2)-α-l-arabinopyranosyl-30-norlean-12,20 (29) –dien-28-olic acid, ciwujianoside E, guaianin N, and eleutheroside K. The chromatographic separation was performed using an ACQUITY UPLC BEH C18 column (2.1 × 100 mm, 1.7 μm) using a gradient elution way with a mobile phase of acetonitrile-water containing 0.1% formic acid. Analytes were detected on a triple-quadrupole mass spectrometer equipped with an electrospray ionization (ESI) source with multiple reaction monitoring (MRM) mode. Calibration curves were all linear (r ≥ 0.9933) over the concentration range. The mean extraction recoveries and matrix effect of analytes and I.S. were ranged from 80.26% to 98.32% and from 91.27% to 111.67%, respectively. The intra-day and inter-day precision were ranged from 2.20% to 14.81%, and the accuracy range was 1.60–14.60%. The analytical method was successfully applied for the pharmacokinetic characteristics of the six analytes in beagle plasma after oral administration of ESL extracts. The T 1/2 of six analytes was more than 3.09 ± 0.78 h.

Abstract

A rapid and simple ultra-performance liquid chromatography-electrospray ionization-tandem mass spectrometry (UPLC-ESI-MS/MS) method was developed and validated for simultaneous determination of six analytes from the Eleutherococcus senticosus (Rupr. & Maxim.) Maxim. leaves (ESL) in beagle dog plasma for the first time, including 3-O-α-l-rhamnopyranosyl-(1→2)-α-l-arabinopyranoside-29-hydroxy oleanolic acid, 3-O-β-d-glucopyranosyl-(1→2)-α-l-arabinopyranoside-29-hydroxy oleanolic acid, 3-O-β-d-glucopyranosyl-(1→2)-α-l-arabinopyranosyl-30-norlean-12,20 (29) –dien-28-olic acid, ciwujianoside E, guaianin N, and eleutheroside K. The chromatographic separation was performed using an ACQUITY UPLC BEH C18 column (2.1 × 100 mm, 1.7 μm) using a gradient elution way with a mobile phase of acetonitrile-water containing 0.1% formic acid. Analytes were detected on a triple-quadrupole mass spectrometer equipped with an electrospray ionization (ESI) source with multiple reaction monitoring (MRM) mode. Calibration curves were all linear (r ≥ 0.9933) over the concentration range. The mean extraction recoveries and matrix effect of analytes and I.S. were ranged from 80.26% to 98.32% and from 91.27% to 111.67%, respectively. The intra-day and inter-day precision were ranged from 2.20% to 14.81%, and the accuracy range was 1.60–14.60%. The analytical method was successfully applied for the pharmacokinetic characteristics of the six analytes in beagle plasma after oral administration of ESL extracts. The T 1/2 of six analytes was more than 3.09 ± 0.78 h.

1 Introduction

Eleutherococcus senticosus (Rupr. & Maxim.) Maxim. Leaves (ESL) has been officially recorded as an official health function drug by the China Food and Drug Administration, it was documented in the ancient Chinese medical book “Rihuazi Materia Medica”. And they are widely distributed in northeast China, Japan, northeast Russia. ESL are used for spleen and lung qi deficiency, physical weakness, loss of appetite, lung and kidney deficiency, chronic cough and asthma, waist and knee pain, heart and spleen deficiency, insomnia, dreaminess [1–3] in aspect of Traditional Chinese Medicine (TCM). ESL was often produced as dietary supplement and tea. The tea of ESL has been used to treat chronic diseases like insomnia and diabetes [4, 5]. The young leaves of ESL have been used as a kind of edible vegetable and abortion for more than thousands of years.

ESL is mainly rich in triterpene saponins [6–11], flavonoids [12] and organic acids [13]. Saponin glycosides is its main active ingredient. In the in-depth development of ESL, many researchers have studied more on saponins active ingredients. In the preliminary study, we studied its main chemical components and pharmacological effects. Six triterpene saponins were isolated from ESL in preliminary research, including 3-O-α-l-rhamnopyranosyl-(1→2)-α-L-arabinopyran Fructoside-29-hydroxyoleanolic acid (1), 3-O-β-d-glucopyranosyl-(1→2) -α-l-arabinopyranoside-29-hydroxyolean Acid (2), 3-O-β-d-glucopyranosyl-(1→2)-α-l-arabinopyranosyl-30-norlean-12,20 (29) -dien-28-olic acid (3), eleutheroside E (4), guaianin N (5) and eleutheroside K (6). Among them, 4 has activities in treating diabetes, inflammatory activities [14–15]. 5 had been reported to had weak inhibitory effect on nitric oxide production by lipopolysaccharide (LPS)-activated macrophage 264.7 anti-tumor effects [16–17], and anti-HIV, and anti-bacterial activity against pseudomonas and brine shrimp toxicity [18]. 6 has been reported to possess antispasmodic [19], anti-leishmanicidic [20], pro-apototic and anti-cancer activities [21]. In particularly, 6 has no cytotoxic effect [22], but it could reverse chemotherapy resistance of breast cancer cells by reducing the formation and releases of D/exo, reversing docetaxel resistance [23]. Little research has been done on 1, 2, and 3. To the best of our knowledge, these six triterpene saponins have not been clinically used as drugs, nor have their metabolism been studied in vivo. Pharmacokinetics studies on ESL active ingredients would be helpful to study the efficacy and toxicity of ESL. At present, there are no pharmacokinetic studies on saponins from ESL have been reported, mainly because the molecular weight of saponins is large and it is difficult to detect in plasma [24]. In this study, a highly sensitive, novel method for simultaneously determination of the six triterpenoid saponins in Beagle dog plasma was established by ultra-performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS).

2 Experimental

2.1 Chemicals and reagents

The reference standards for 3-O-α-l-rhamnopyranosyl-(1→2)-α-l-arabinopyranoside-29-hydroxy oleanolic acid (1), 3-O-β-d-glucopyranosyl-(1→2)-α-l-arabinopyranoside-29-hydroxy oleanolic acid (2), 3-O-d-glucopyranosyl-(1→2)-α-l-arabinopyranosyl-30-norlean-12,20 (29)-dien-28-olic acid (3), eleutheroside E (4), guaianin N (5), eleutheroside K (6) were isolated from ESL, in pre-experiment, and based on the UV, NMR, MS, HPLC analysis, the chemical structures were identified. All purities were more than 98.0%. Butylparaben as internal standard (I.S.) (NO. 3801-2010, purity >98%) was purchased from the Tianjin Kermel (Tianjin, China). All HPLC-grade chemical reagents (methanol, acetonitrile, formic acid, and acetic acid) were purchased from Thermo Fisher Scientific (Shanghai, China). Analytical-grade dichloromethane, isopropyl-alcohol and ethyl acetate n-butanol was purchased from Xilong Scientific (Guangdong, China). The Millipore Milli-Q Plus system (Millipore Inc, Molsheim, France) was used to prepare deionized water, which was prepared from Watsons water (Guangzhou, China).

2.2 Equipment and UPLC-MS/MS conditions

Chromatographic separation was carried out on Waters ACQUITY UPLC system (Waters Inc. Milford, MA, USA) using an ACQUITY UPLC BEH C18 (2.1 × 100 mm, 1.7 μm) column. The gradient mobile phase system was composed of solution A (0.1% formic acid-water) and solution B (0.1% formic acid - acetonitrile), which was distributed at a flow rate of 0.4 mL min−1. The gradient elution was 50%–50% B at 0.0–0.5 min, 50%–70% B at 0.5–1.0 min, 70%–70% B at 1.0–1.5 min, 70%–90% B at 1.5–4.0 min, 90%–90% B at 4.0–5.0 min. The elution time was 5.0 min. The temperature of column and the auto-sampler were at were 40°C and 10°C, respectively. The auto-sampler takes about 10 μl sample for injection.

UPLC system was connected to an AB Sciex 4000 triple quadrupole tandem mass spectrometer (AB Sciex Inc, Toronto, ON, Canada). The ion source was electrospray ionization (ESI) interface (Framingham Inc, MA, USA). The quantitative analyte detection was performed by using multiple reaction monitoring (MRM) in negative mode. The transitions of precursor-product ion at m/z 749.4→471.3 for 1, 765.6→603.6 for 2, 733.4→571.4 for 3, 717.4→439.3 for 4, 749.9→587.7 for 5, 733.3→455.3 for 6, and 193.0→92.0 for I.S., respectively. The parameters of the source were set as follows: ionspray voltage 4500 V; capillary temperature 450°C; ion source gas 1 (GS1) flow 50 psi; ion source gas 2 (GS2) flow 50 psi; curtain gas flow 10 psi, the dwell time 100 ms. The declustering potential (DP) was 205.6 V for 1, 189.48 V for 2, 228.68 V for 3, 183.15 V for 4, 217.18 V for 5, 191.59 V for 6, and 98.32 V for butylparaben, respectively. The nebulizing gas was Liquid nitrogen (N2), the drying gas was nitrogen (N2). The operating conditions are the flow rate of 400 L h−1 and the temperature of 40°C.

2.3 Preparation of ESL extract

ESL were collected in August from the Medicinal Botanical Garden of Heilongjiang University of Chinese Medicine (Harbin, Heilongjiang province, China) and identified by Professor Zhenyue Wang. The leaves (13.0 kg) were extracted with 130 L methanol (1:10, w/v) for 2 h, thrice in total, and then filtered by using gauze, concentrated to dryness under reduced pressure by rotary evaporation apparatus, and the residues were passed through an AB-8 microporous resin column (H2O – 30% EtOH – 60%). Finally, 60% of the ethanol component were drying after lyophilized. Then the extract of ESL was obtained.

The contents of the six compounds in ESL were quantified by using a HPLC-ELSD method in order to calculate the administration. The concentrations of the six analytes were 14.03 μg g−1 for 1, 26.83 μg g−1 for 2, 6.76 μg g−1 for 3, 9.38 μg g−1 for 4, 15.56 μg g−1 for 5, 34.20 μg g−1 for 6, respectively.

2.4 Preparation of calibration and quality control samples

A mixed stock solution was prepared by dissolving the mixed standard with methanol, and the standard working solutions of concentration that was 210.2 μg mL−1 for 1, 201.6 μg mL−1 for 2, 250.0 μg mL−1 for 3, 220.2 μg mL−1 for 4, 225.6 μg mL−1 for 5 and 230.0 μg mL−1 for 6. Standard working solutions were acquired by further diluting the stock solution with methanol. Internal standard solution (200.0 ng mL−1) was obtained through further dilution of stock solution (600.0 ng mL−1) with methanol.

The final concentrations of 1 were 0.6570–210.2 ng ml; 0.6300–201.6 ng ml−1 for 2; 0.7815–250.0 ng mL−1 for 3; 0.6880–220.2 ng mL−1 for 4; 0.7050–225.6 ng mL−1 for 5; 0.7190–230.0 ng mL−1 for 6. Quality control (QC) samples at four concentration levels: LLOQs, LQCs, MQCs and HQCs were prepared in the same way, 0.6570, 1.314, 84.08, and 168.16 ng mL−1 for 1, 0.6300, 1.260, 80.64 and 161.28 ng mL−1 for 2, 0.7815, 1.563, 100.0 and 200.0 ng mL−1 for 3, 0.6880, 1.376, 88.08, and 176.16 ng mL−1 for 4, 0.7050, 1.410, 90.24, and 180.48 ng mL−1 for 5, and 0.7190, 1.438, 92.00, and 184.00 ng mL−1 for 6. All the standard working solutions were prepared on site, and stored at -20 °C.

2.5 Preparation of samples

Six male beagle dogs (body weight 9.95 ± 0.77 kg, age 4 ± 1.0 years old) were purchased from Shenyang Kangping Experiment Animal Research Institute. The animal license number was SCXK 2014–0003. The six beagle dogs were raised in the Experimental Animal Center of Heilongjiang University of Chinese medicine (Harbin, China). All the experimental behaviors and operations were approved by the Institutional Ethics Committee of Heilongjiang University of Chinese medicine (Harbin, China). The experimental operation was carried out according to the Laboratory Animals Guidelines for Ethical Review of Welfare (GB/T 35,892–2018). The purpose of this study was to compare the experimental methods of 6 target analytes after oral ESL in beagle dogs and to investigate their pharmacokinetic characteristics. In the future, we will expand the sample size for further research and confirmation of the results. Dogs were reared under appropriate conditions, with relative humidity of 60 ± 5%, room temperature of 22 ± 2°C and light conditions consistent with circadian rhythm. While acclimating to the environment, dogs were kept on ordinary clean grade diet for 3 days, fasted for 12 h and free water before administration. 2 mL of blood sample was drawn from forearm vein at following time points (0, 0.25, 0.50, 1.00, 1.50, 2.00, 2.50, 3.00, 4.00, 6.00, 8.00, 12.00 and 24.00 h) after oral administration of ESL into 5 mL heparinized polythene tubes. The blood samples were immediately centrifuged at 3500 RPM for 25 min at 4°C. The separated plasmas were stored at −20°C until analysis. The plasma concentration time data for the six analytes in plasma were calculated by the software DAS 2.1 (Mathematical Pharmacology Professional Committee of China, Shanghai, China) in non-compartmental mode. The results were expressed as mean ± SD.

The 100 μL plasma samples were placed in 5 mL centrifuge tubes, and then 250 μL methanol, 50 μL acetonitrile, and 100 μL I.S. solution were added into the centrifuge tubes. The solution obtained from the previous step were vortex-mixed for 2 min, followed by ultrasonic oscillation for 1 min, ethyl acetate-isopropanol (1:1) was added, and then vortexed for 2 min. The solution was then centrifuged at 1300 RPM for 15min and the supernatant was collected into 1.5 mL centrifuge tubes, evaporated at 40°C under a pure nitrogen stream and the residue was reconstituted in 100 μL of methanol. After swirling for 1 min, the mixture was transferred into a 1.5 mL centrifuge tube, centrifuged at 13,000 RPM at 4°C for 10 min, and finally the supernatant was filtered through a 0.22 µm membrane.

2.6 Method validation

The developed bioanalytical method was validated according to the principles of Guidance for Industry Bioanalytical Method Validation by the US Food and Drug Administration (FDA), considering selectivity, linearity, precision, accuracy, extraction recovery, matrix effect, and stability [25].

2.6.1 Selectivity

By comparing the plasma samples of six different batches of blank dog, the blank plasma was spiked with the analytes and I.S., and the chromatogram of the plasma samples was collected for 2.5 h after the ESL extract was taken orally for comparison. Endogenous interference was analyzed in the plasma of the blank beagle dogs, followed by spiking with I.S. for the interference of I.S.

2.6.2 Linearity and lower limits of quantification (LLOQ)

The linearity of calibration curve was determined by plotting the peak area ratio (Y) of analytes to I.S. versus the nominal concentration (X) of the analytes with weighted (1/X 2) least-squares linear regression. The sensitivity of the method was calculated by LLOQ, which was the lowest concentration on the calibration curve at which the signal-to-noise ratio (S/N) ≥ 10.

2.6.3 Precision and accuracy

The intra-day precision and accuracy were evaluated at LLOQ, LQC, MQC, HQC concentration levels of the analytes in six replicates on the same day and analyzed continuously for three days. Similarly, the inter-day precision and accuracy of the analyte were measured at four concentration levels over six replicates over three consecutive days.

The precision was expressed as a percentage relative SD (RSD%), which was the ratio of the SD to the arithmetic mean of the measurement results. The precision was illustrated as a relative error (RE), which should be within ±15%.

2.6.4 Extraction recovery and matrix effect

The extraction recoveries were assessed by comparing the mean peak areas of analytes obtained from QC samples with those obtained from pure reference standards spiked in post-extracted blank plasma at LQC, MQC, HQC levels. The matrix effect was assessed by comparing the peak area of an analyte added to the extracted supernatant with that of a standard solution containing an analyte of the same concentration.

2.6.5 Stability

The stability of the analytes was evaluated in dog plasma at LQC, MQC, HQC concentrations levels in dog plasma under the following conditions (n = 6). The short-term stability of blood samples was investigated by storing them at room temperature (25 °C) for 4 h. And the long-term stability was evaluated for kept at −20 °C for 4 weeks. In addition, the freeze-thaw stability was tested after three complete freeze/thaw cycles (−20°C–25°C) on consecutive days. And the post-preparation stability was evaluated after placed in the auto-sampler (10 °C) for 24 h before analyze. It can be considered that the analytes were stable when the deviation less than ±15%. The calibration curve of the newly developed standard is used to test all the tested QC samples.

3 Results and discussion

3.1 Optimization of the UPLC-MS/MS condition

MS/MS parameters were optimized for determination of the analytes and I.S. According to the previously reported, negative mode was applied for triterpenoids ion monitoring. The positive and negative mode were investigated to obtain the precursor and product ion, the response of the analytes observed in the negative ionization mode was higher than that in positive ionization mode. Therefore, the negative ion mode was selected for the MS/MS detection. And the response of the analytes observed in the negative mode was stable. The electrospray ionization (ESI) source was used as ionization interface. The optimization of MS/MS parameters were accomplished by the manual turning tool to obtain optimal sensitivity of product ion of analytes and I.S. The optimized mass transitions ion pairs of the precursor to production were ascertained for MRM. All the products and qualifier ions were selected basing on the stability and high ion response. The optimized mass transitions ion pairs and parameters are listed in Table 1. MS/MS fragmentation patterns of the six analytes and I.S. are illustrated in Fig. 1.

Table 1.

Precursor/production pairs and parameters for MRM of analytes

Analyte Ionization mode Precursor Product Qualifier DP (V) CE (V)
Ion (m/z) Ion (m/z) Ion (m/z)
1 negative 749.4 471.3 587.3 −205.60 −59.14
2 negative 765.6 603.1 585.4 −189.48 −57.34
3 negative 733.4 571.4 587.7 −228.68 −55.06
4 negative 717.4 439.3 571.1 −183.15 −58.75
5 negative 749.9 587.7 471.3 −217.18 −59.35
6 negative 733.3 455.3 587.2 −191.59 −61.10
I.S. negative 193.0 92.0 135.9 −98.32 −33.74
Fig. 1.
Fig. 1.

Product ion mass spectra of 3-O-α-l-rhamnopyranosyl-(1→2)-α-l-arabinopyranoside-29-hydroxy oleanolic acid (A), 3-O-β-d-glucopyranosyl-(1→2)-α-l-arabinopyranoside-29-hydroxy oleanolic acid (B), 3-O-β-d-glucopyranosyl-(1→2)-α-l-arabinopyranosyl-30-norlean-12,20 (29) –dien-28-olic acid (C), eleutheroside E (D), guaianin N (E), eleutheroside K (F), and I.S. (G)

Citation: Acta Chromatographica 2022; 10.1556/1326.2022.01011

3.2 Optimization of chromatography

Two organic phases consist of acetonitrile and methanol were tested, respectively. The responses of analytes and I.S. were higher with acetonitrile-water as mobile phase than that methanol-water through a series of trials. The 0.1% formic acid can improve the peak shape and the mass response. To eliminate the undesirable crosstalk effects and achieve a complete chromatographic resolution, we shorten the analysis time and increased the peak capacity within 3.0 min [26]. The flow rate and column temperature were adjusted to acquire a great resolution with no crosstalk observed. Finally, the separation was carried out by gradient elution at column temperature 40°C consisting of acetonitrile-water added 0.1% formic acid at a flow rate of 0.4 mL min−1. There was no carry-over effect detected above method.

3.3 Optimization of extraction method

In order to obtain high extraction recovery and little endogenous interference at the retention time, several solvents such as methanol, acetonitrile, methanol-acetonitrile were investigated by precipitation of protein (PPT) in dog plasma. PPT with methanol-acetonitrile (v:v, 5:1) were to increase the extraction rate of the six triterpenoid saponins and reduce the matrix effect. It was illustrated that methanol-acetonitrile for PPT produced the best extraction recovery for all the analytes and I.S. Finally, plasma samples were prepared with methanol-acetonitrile (v:v, 5:1) precipitation for lowest noise interference level.

3.4 Selection of I.S

An ideal I.S. should be a stable isotope-labeled compound or structurally similar compound [27]. Butylparaben was selected as the I.S. because of its high mass spectral response and good chromatographic peak shape. Furthermore, the retention time of butylparaben was stable in the above liquid phase conditions, and little interference was detected in plasma.

3.5 Method validation

3.5.1 Selectivity

The selectivity of the method was evaluated with plasma in contrary to endogenous plasma matrix from six beagle dogs. Under the developed UPLC-MS/MS conditions, all the analytes could be separated and quantitatively determined at LLOQ and MQC levels. The retention time of six analytes and I.S. was 0.98 min for 1, 0.85 min for 2, 2.01 min for 3, 2.23 min for 4, 2.40 min for 5, 2.65 min for 6, and 1.90 min for I.S., respectively. There was no significant interference observed at the retention time of the analytes and I.S. The Respective chromatograms of blank plasma, plasma sample spiked with the analytes and I.S., and the plasma sample gained from dog after oral administration of the total saponin of ESL are shown in Fig. 2.

Fig. 2.
Fig. 2.

Respective MRM Chromatograms of 1 (1), 2 (2), 3 (3), 4 (4), 5 (5), 6 (6) and I.S. (7): (a) blank plasma, (b) blank sample spiked with the analytes at LLOQ and I.S., (c) blank sample spiked with the analytes at MQC and I.S., (d) sample from beagle dogs at 2.5 h after oral administration of ESL extract

Citation: Acta Chromatographica 2022; 10.1556/1326.2022.01011

3.5.2 Linearity and lower limit of quantification

The regression equation, correlation coefficients and linearity ranges for the six analytes are shown in Table 2. The linear calibration ranges were 0.6570–210.2 ng mL−1 for 1, 0.6300–201.6 ng mL−1 for 2, 0.7815–250.0 ng mL−1 for 3, 0.6880–220.2 ng mL−1 for 4, 0.7050–225.6 ng mL−1 for 5, 0.7190–230.0 ng mL−1 for 6, respectively. The correlation coefficients were high than 0.9933. The results revealed that there was great correlation between the peak area ratio of analytes to I.S. and concentration within the linearity ranges. The LLOQs was 0.6570 ng mL−1 for 1, 0.6300 ng mL−1 for 2, 0.7815 ng mL−1 for 3, 0.6880 ng mL−1 for 4, 0.7050 ng mL−1 for 5, 0.7190 ng mL−1 for 6, respectively.

Table 2.

The regression equations, linear ranges, LLOQs of analytes

Compound Linear Regression Equation Linear Range (ng mL−1) r LLOQ (ng mL−1)
1 Y = 2.02 × 10−4 X + 4.0 × 10−4 0.6570–210.2 0.9956 0.6570
2 Y = 5.01 × 10−4 X + 9.0 × 10−4 0.6300–201.6 0.9962 0.6300
3 Y = 6.22 × 10−3 X – 4.2 × 10−3 0.7815–250.0 0.9987 0.7815
4 Y = 1.10 × 10−3 X – 1.3 × 10−3 0.6880–220.2 0.9981 0.6880
5 Y = 7.04 × 10−4 X – 1.2 × 10−3 0.7050–225.6 0.9956 0.7050
6 Y = 1.20 × 10−3 X – 3.0 × 10−4 0.7190–230.0 0.9933 0.7190

3.5.3 Precision and accuracy

The intra-day and inter-day precisions and accuracies were evaluated by determination of QC samples at LLOQ, LQC, MQC, HQC levels in six replicates on a same day and on three consecutive validation days, respectively. The results of precision and accuracy of all the analytes are shown in Table 3. The intra-day and inter-day precisions ranged from 2.20 to 14.81% and 2.21–14.80%, respectively. The accuracies were from −1.60% to 14.60%. The assay values on precision and accuracy were within the acceptable range (<15%). These results demonstrated an excellent precision and accuracy for the quantification of the six analytes in plasma.

Table 3.

Precision and accuracy for the determination of the 6 triterpenoid saponins in dog plasma (n = 6)

Compound Spiked Concentration (ng ml−1) Mean ± SD (ng ml−1) Intra-day Precision RSD (%) Inter-day Precision RSD (%) Accuracy RE (%)
1 0.6570 0.6600 ± 0.32 6.30 8.20 −10.40
1.314 1.5000 ± 0.12 7.60 12.00 14.60
84.08 81.27 ± 5.81 7.30 13.30 2.50
168.16 167.10 ± 3.53 6.80 9.50 −3.20
2 0.6300 0.6300 ± 0.10 4.20 5.30 10.20
1.260 1.3540 ± 0.07 5.50 2.21 8.20
80.64 80.59 ± 4.03 9.20 14.80 1.80
161.28 162.73 ± 4.10 4.80 6.20 0.70
3 0.7815 0.7855 ± 0.42 3.21 2.10 −3.00
1.563 1.7220 ± 0.27 14.81 12.3 10.40
100.00 96.59 ± 5.63 2.20 3.80 −1.60
200.00 199.21 ± 1.19 6.4 6.90 −3.80
4 0.6880 0.6900 ± 0.19 4.50 6.20 2.10
1.376 1.2601 ± 0.19 13.5 14.1 −1.70
88.08 86.26 ± 11.41 7.90 8.90 3.70
176.16 175.12 ± 3.68 13.5 10.80 −2.00
5 0.7050 0.7100 ± 0.50 5.10 8.70 −3.40
1.410 1.5455 ± 0.12 6.80 11.70 6.80
90.24 90.01 ± 5.14 5.30 11.60 1.90
180.48 177.89 ± 2.99 5.40 7.70 −2.20
6 0.7190 0.7201 ± 0.11 6.00 5.03 −2.30
1.438 1.6012 ± 0.13 8.00 8.10 11.40
92.00 90.47 ± 5.66 12.20 5.30 7.10
184.00 180.25 ± 5.70 6.30 6.30 −1.70

3.5.4 Extraction recovery and matrix effect

The extraction recoveries and matrix effects of the six analytes at three QC concentration levels are displayed in Table 4. The extraction recoveries of the six analytes from beagle dog plasma were 80.26–98.32% at three QC levels (LQC, MQC, HQC), and the mean matrix effect in plasma ranged from 93.39% to 111.67% for the six analytes at three QC levels. The averaged extraction recovery and matrix effect of I.S. were 98.40% and 91.27%, respectively. The results indicated that the recovery rate of PPT procedure in dog plasma was satisfactory for all analytes and there no endogenous substances obstruct the determination of the analytes.

Table 4.

The averaged extraction recoveries and matrix effects of the 6 triterpenoid saponins and I.S. in dog plasma (n = 6)

Compound Concentration (ng mL−1) Recovery Matrix effect
Mean (%) RSD (%) Mean (%) RSD (%)
1 1.314 98.32 14.74 98.99 2.87
84.08 94.69 4.26 97.86 4.49
168.16 90.98 10.68 105.18 14.82
2 1.260 97.99 4.62 95.63 0.75
80.64 96.77 14.58 93.39 1.15
161.28 84.06 6.68 102.83 4.85
3 1.563 92.64 13.85 95.05 5.92
100.00 86.61 7.22 110.12 9.86
200.0 88.58 11.52 107.92 7.12
4 1.376 97.23 3.70 93.11 0.44
88.08 87.81 4.12 95.09 2.01
176.16 90.92 10.36 100.37 6.52
5 1.410 94.21 5.37 94.22 2.89
90.24 93.69 3.75 93.69 4.39
180.48 89.90 14.97 111.67 14.16
6 1.438 80.26 13.15 97.83 2.74
92.00 82.01 7.82 111.40 7.03
184.00 83.04 13.14 104.41 12.48
I.S. 200.00 98.40 11.06 91.27 3.71

3.5.5 Stability

Stability of the six analytes were evaluated under four storage conditions at three QC levels. The results were presented in Table 5. The results indicated that the plasma samples were stored at room temperature (25°C) for 4h, at −20°C for one month, and in the automatic sampler (10°C) for 24h. The plasma samples were stable during three-free thaw cycles, and the accuracy was in the range of −14.82–14.91%. The results were within the acceptance limits of ±15%.

Table 5.

Stability of the 6 triterpenoid saponins in dog plasma (n = 6)

Compound Concentration (ng mL−1) Stability (% RE)
Short-term storage (4h at room temperature) Freeze-thaw cycles (−20–25 °C) Long-term storage (a month at −20 °C) Post-preparative (24h at 10 °C)
1 1.314 5.07 2.21 2.65 3.65
84.08 −11.99 4.04 5.64 10.94
168.16 10.3 4.02 3.47 4.29
2 1.260 2.24 −0.355 −0.56 4.87
80.64 13.31 −3.00 −7.41 4.87
161.28 12.58 1.04 3.42 −5.59
3 1.563 6.82 5.96 3.52 4.08
100.00 −9.21 −12.06 −0.34 −3.75
200.00 −7.6 −14.49 −13.49 −3.39
4 1.376 14.18 1.15 6.637 1.015
88.08 −7.24 −14.94 8.51 4.64
176.16 −3.64 −13.36 1.322 3.34
5 1.410 5.13 2.52 12.57 14.64
90.24 −13.11 14.88 13.82 4.58
180.48 −8.14 −13.74 −8.38 −14.82
6 1.438 3.58 14.91 13.05 4.397
92.00 10.017 −10.31 13.66 10.04
184.00 0.224 −6.62 −14.43 −2.76

3.6 Pharmacokinetic study

The validated method was successfully applied to the pharmacokinetic study in plasma after the oral administration of the ESL extract at a dose of 0.84 g kg−1 to the beagle dog. The dog dosage used was converted from the human dosage recorded in the Chinese pharmacopoeia [28]. The typical plasma concentration-time profiles of the analytes are shown in Fig. 3 (see Fig. 1). The pharmacokinetic parameters including the half-time (T 1/2), the maximum plasma concentration (C max), the time to reach the maximum concentrations (T max), elimination rate constants (Ke), area under concentration-time curve (AUC0-t, AUC0-∞) are shown in Table 6.

Fig. 3.
Fig. 3.

Mean plasma concentration-time profiles of the six analytes in beagle dog plasma after oral administration of administration of the extract of ESL. (A): 1, (B): 2, (C): 3, (D): 4, (E): 5, (F): 6

Citation: Acta Chromatographica 2022; 10.1556/1326.2022.01011

Table 6.

Main pharmacokinetic parameters of the six analytes after oral administration of ESL to beagle dogs (mean ± SD, n = 6)

Analytes Parameters
C max (ng mL−1) T max (h) T 1/2 (h) AUC0-t (ngmL−1h) AUC0-∞(ngmL−1h)
1 53.78 ± 7.14 1.70 ± 0.36 3.27 ± 0.72 229.08 ± 42.40 253.43 ± 55.93
2 38.72 ± 12.59 2.51 ± 0.05 3.12 ± 1.20 157.25 ± 40.17 173.16 ± 55.72
3 50.01 ± 7.59 2.30 ± 0.24 3.09 ± 0.78 181.81 ± 15.02 198.93 ± 25.46
4 49.13 ± 15.65 2.39 ± 0.17 3.89 ± 0.35 193.83 ± 70.01 222.15 ± 84.28
5 30.63 ± 5.07 2.66 ± 0.02 4.01 ± 3.62 140.88 ± 29.75 180.82 ± 6.45
6 79.57 ± 5.66 2.50 ± 0.41 3.90 ± 1.17 436.31 ± 65.34 518.19 ± 181.29

The T max of 1, 2, 3, 4, 5 and 6 were 1.70 ± 0.36, 2.51 ± 0.05, 2.30 ± 0.24, 2.39 ± 0.17, 2.66 ± 0.02, and 2.50 ± 0.41 h, respectively. The T max ranged 1.70–2.66 h, which indicated the absorption of the components (except 1) was relatively slow. The reason might be due to the molecular masses of the six saponins larger than 700 Da (the favorable value) [29]. The T max required for 2 and 5 was significantly more than for other analytes, perhaps related to their substituent's arabinose and glucose, and the T max of 6 was slightly less than the T max of 2 and 5. Perhaps related to the substitution of two arabinoses. The T 1/2 of 1, 2, 3, 4, 5 and 6 were 3.27 ± 0.72, 3.12 ± 1.20, 3.09 ± 0.78, 3.97 ± 0.35, 4.01 ± 3.62, and 3.90 ± 1.17 h, respectively. Both T max and T 1/2 of 5 and 6 were higher than other analytes, which demonstrated that low absorption of 5 and 6. By the way, this may be related to their Angular methyl of C-20. The former results indicated that the metabolism of the six analytes were different in vivo. The difference might be related with different substituents groups' chemical structure. The differences of the C max of six analytes maybe concerned with their contents in ESL. The AUC0-∞ ranged from 173.16 ± 55.72 to 518.19 ± 181.29 ngh−1mL, and the AUC0-t ranged from 140.88 ± 29.75 to 436.31 ± 65.34 ngh−1mL, which corresponded to administration dosage and excretion. Both T 1/2 and AUC0-∞ increased slightly, inferring that the six saponins have a similarly slow distribution and slow elimination process, and it is likely to accumulate in vivo [30]. These results would be sense to further studies on the pharmacokinetics, toxicity, and pharmacology of ESL and promote research into the efficacy of the TCM herb in clinical therapeutic studies.

4 Conclusion

A rapid and selective UPLC-MS/MS method was developed for the simultaneous determination of six compounds of ESL in beagle dog plasma. The beagle dogs were used as experimental animals. It was successfully investigated the pharmacokinetics of the six triterpenoid saponins of ESL in beagle plasma. The pharmacokinetics parameters of the six analytes showed a process of similarly slow absorption and quick elimination in the body. The results were helpful for the clinical application of ESL, and provided a foundation for further research on the pharmacology mechanisms and toxicology of ESL.

Data availability

The data used to support the findings of this study are included within the manuscript and are available from the corresponding author upon request.

Conflicts of interest

The authors declare no conflict of interest.

Author's contributions

Zhibin Wang conceived the experiments; Feng Cao and Yaodan Chang designed and performed the experiments; Yaodan Chang analyzed the data; Zhibin Wang contributed reagents/materials/analysis tools; Yaodan Chang and Zhenyue Wang wrote the paper. Chunjuan Yang, Haixue Kuang Polish the paper. All authors read and approved the final manuscript.

Acknowledgments

All work was supported by R & D and Demonstration of Ecological Forest Exploitation and Utilization Technology of Forest Drugs in Northeast Forest Region (No. 2016YFC0500303), The National Science and Technology Key Project and Key Research and Development Project of Heilongjiang province (No. GX17C006), Heilongjiang Provincial Postdoctoral Funding Project (No. LBH-Z17208), Postdoctoral Research Initiative Funding Project of Heilongjiang Province (No. LBH-Q16214), Heilongjiang Provincial Science Fund Project (No. H2018056), National Natural Science Foundation project (No. 81973439), Heilongjiang Provincial Department of Education Project (No. 12511512) and Research Project of “Excellent Innovative Talent Support Program” of Heilongjiang University of Chinese Medicine (No. 2018RCD03) Heilongjiang Touyan Innovation Team Program (Document of Heilongjiang Head Goose Action Leading Group (2019) No.5.

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    Tu, Z. W. ; Zhou, W. W. ; Shan, Q. ; Xin, N. ; Hou, W. B. Advances in studies on chemical constituents of Acanthopanax senticosus and their pharmacological effects. Drug Eval. Res. 2011, 34, 213216.

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    • Export Citation
  • 3.

    Gao, H. ; Xu, W. ; Zhang, Y. H. ; Qiu, Z. D. ; Fu, C. M. ; Qi, X. N. ; Jia, A. L. Anti-fatigue mechanism of Acanthopanax senticosus glycosides based on network pharmacology. Chin. Traditional Herbal Drugs 2021, 52(2), 413421.

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    Wang, Y. H. ; Zhai, C. M. ; Wang, M. ; Bharathi, A. ; Jimmy, Y. ; Kerri, M. S. ; Giorgis, I. ; Ikhlas, A. K. The chemical characterization of Eleutherococcus senticosus and Ci-Wu-jia tea using UHPLC-UV-QTOF/MS. Int. J. Mol. Sci. 2019, 20(3), 475.

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  • 5.

    Ge, Y. W. ; Zhu, S. ; Yoshimatsu, K. ; Komatsu, K. MS/MS similarity networking accelerated target profiling of triterpene saponins in Eleutherococcus senticosus leaves. Food Chem. 2017, 227, 444452.

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    • Export Citation
  • 6.

    Shao, C. J. ; Kasai, R. ; Xu, J. D. ; Tanaka, O. Saponins from leaves of acanthopanax senticosus harms., Ciwujia. II. Structures of ciwujianosides A1, A2, A3, A4 and D3. Chem. & Pharm. Bull. 1989, 37, 4245.

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    • Export Citation
  • 7.

    Shao, C. J. ; Kasai, R. ; Xu, J. D. ; Tanaka, O. Saponins from leaves of acanthopanax senticosus harms., Ciwujia: structures of ciwujianosides B, C1, C2, C3, C4, D1, D2 and E. Chem. & Pharm. Bull. 1988, 36, 601608.

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    Xia, Y. G. ; Gong, F. Q. ; Guo, X. D. ; Song, Y. ; Li, C. X. ; Liang, J. ; Yang, B. Y. ; Kuang, H. X. Rapid screening and characterization of triterpene saponins in Acanthopanax senticosus leaves via untargeted MSAll and SWATH techniques on a quadrupole time of flight mass spectrometry. J. Pharm. Biomed. Anal. 2019, 170, 6882.

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    • Search Google Scholar
    • Export Citation
  • 9.

    Jiang, W. H. ; Li, W. ; Han, L. K. ; Liu, L. J. ; Zhang, Q. B. ; Zhang, S. J. ; Nikaido, T. ; Koike, K. Biologically active triterpinoid saponins from Acanthopanax senticosus. J. Nat. Prod. 2006, 69, 15771581.

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    • Search Google Scholar
    • Export Citation
  • 10.

    Ling, J. J. ; Lee, S. ; Lee, Y. Y. ; Kim, J. M. ; Heo, J. E. ; Yun-Choi, H. S. Platelet anti-aggregating triterpeniods from the leaves of Acanthopanax senticosus and the fruits of Acanthopanax sessiliflorus. Planta Med. 2004, 70, 564566.

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    • Search Google Scholar
    • Export Citation
  • 11.

    Park, S. ; Chang, S. ; York, C. ; Nohara, T. New 3, 4-seco-lupane-type triterpene glycosides from Acanthopanax senticosus forma inermis. J. Nat. Prod. 2000, 63, 16301633.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 12.

    Chen, M. L. ; Song, F. R. ; Guo, M. Q. ; Liu, Z. Q. ; Liu, S. Y. Identification of the flavonoid constituents from leaves of acanthopanax senticosus harms. Chem. Res. Chin. Universities 2002, 5, 805808.

    • Search Google Scholar
    • Export Citation
  • 13.

    Cheng, H. C. ; Wei, W. F. ; Huo, J. H. ; Sun, G. D. ; Wang, W. M. Identification of chemical constituents of the leaves from acanthopanax senticosus by UPLC-Q-TOF-MS/MS. Zhong Yao Cai 2016, 39, 15361540.

    • Search Google Scholar
    • Export Citation
  • 14.

    Ahn, J. ; Um, M. Y. ; Lee, H. ; Jung, C. H. ; Heo, S. H. ; Ha, T. Y. ; Eleutheroside, E. An Active Component of Eleutherococcus Senticosus, Ameliorates Insulin Resistance in Type 2 Diabetic Db/db Mice; Evid Based Complement Alternat Med, 2013; pp 934183.

    • Search Google Scholar
    • Export Citation
  • 15.

    He, C. Y. ; Chen, X. H. ; Zhao, C. Y. ; Qie, Y. Y. ; Yan, Z. W. ; Zhu, X. M. Eleutheroside E ameliorates arthritis severity in collagen-induced arthritis mice model by suppressing inflammatory cytokine release. Inflammation 2014, 37, 15331543.

    • Crossref
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    • Export Citation
  • 16.

    Sui, J. J. ; Zhou, W. H. ; Liu, D. Y. ; Li, M. Q. ; Sun, J. S. Highly efficient synthesis of bioactive oleanane-type saponins. Carbohydr. Res. 2017, 452, 4346.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 17.

    Jung, H. J. ; Lee, C. O. ; Lee, K. T. ; Choi, J. ; Park, H. J. Sructure-activity relationship of oleanane disaccharides isolated from Akebia quinata versus cytotoxicity against cancer cells and NO inhibition. Biol. Pharm. Bull. 2004, 27, 744747.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 18.

    Henry, I. C. L. ; Ngeh, J. T. ; Alonso, H. ; Charah, T. W. ; Joseph, B. Anti HIV-1 activity of the crude extracts of Guaiacum officinale L. (Zygophyllaceae). Eur. J. Med. Plants 2014, 4, 483.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 19.

    Trute, A. ; Gross, J. ; Mutschler, E. ; Nahrstedt, A. In vitro antispasmodic compounds of the dry extract obtained from Hedera helix. Planta Med. 1997, 63, 125129.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 20.

    Majester, S. B ; Elias, R. ; Diaz, L. A. M. ; Balansard, G. ; Gasquet, M. ; Delmas, F. Saponins of the ivy plant, Hedera helix, and their leishmanicidic activity. Planta Med. 1991, 57, 260262.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 21.

    Chen, W. X. ; Cheng, L. ; Pan, M. ; Qian, Q. ; Zhu, Y. L. ; Xu, L. Y. ; Ding, Q. D Rhamnose β-Hederin against human breast cancer by reducing tumor-derived exosomes. Oncol. Lett. 2018, 16, 51725178.

    • Search Google Scholar
    • Export Citation
  • 22.

    Park, H. J. ; Kwon, S. H. ; Lee, J. H. ; Lee, K. H. ; Miyamoto, K. ; Lee, K. T. Kalopanaxsaponin A is a basic saponin structure for the anti-tumor activity of hederagenin monodesmosides. Planta Med. 2001, 67, 118121.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 23.

    Cheng, L. ; Xia, T. S. ; Shi, L. ; Xu, L. Y. ; Chen, W. X. ; Zhu, Y. L. ; Ding, Q. D Rhamnose β-hederin inhibits migration and invasion of human breast cancer cell line MDA-MB-231. Biochem. Biophys. Res. Commun. 2018, 495, 775780.

    • Crossref
    • Search Google Scholar
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    He, X. ; Zhang, Y. J. ; Gao, H. ; Li, K. Y. ; Zhang, Y. Z. ; Sun, L. M. ; Tao, G. Z. Simultaneous quantification of picfeltarraenins IA and IB in rat plasma by UPLC-MS/MS: application to a pharmacokinetic study. J. Pharm. Biomed. Anal. 2016, 120, 3237.

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Senior editors

Editor(s)-in-Chief: Kowalska, Teresa

Editor(s)-in-Chief: Sajewicz, Mieczyslaw

Editors(s)

  • Danica Agbaba (University of Belgrade, Belgrade, Serbia)
  • Ivana Stanimirova-Daszykowska (University of Silesia, Katowice, Poland)
  • Monika Waksmundzka-Hajnos (Medical University of Lublin, Lublin, Poland)

Editorial Board

  • R. Bhushan (The Indian Institute of Technology, Roorkee, India)
  • J. Bojarski (Jagiellonian University, Kraków, Poland)
  • B. Chankvetadze (State University of Tbilisi, Tbilisi, Georgia)
  • M. Daszykowski (University of Silesia, Katowice, Poland)
  • T.H. Dzido (Medical University of Lublin, Lublin, Poland)
  • A. Felinger (University of Pécs, Pécs, Hungary)
  • K. Glowniak (Medical University of Lublin, Lublin, Poland)
  • B. Glód (Siedlce University of Natural Sciences and Humanities, Siedlce, Poland)
  • A. Gumieniczek (Medical University of Lublin, Lublin, Poland)
  • U. Hubicka (Jagiellonian University, Kraków, Poland)
  • K. Kaczmarski (Rzeszow University of Technology, Rzeszów, Poland)
  • H. Kalász (Semmelweis University, Budapest, Hungary)
  • K. Karljiković Rajić (University of Belgrade, Belgrade, Serbia)
  • I. Klebovich (Semmelweis University, Budapest, Hungary)
  • A. Koch (Private Pharmacy, Hamburg, Germany)
  • Ł. Komsta (Medical University of Lublin, Lublin, Poland)
  • P. Kus (Univerity of Silesia, Katowice, Poland)
  • D. Mangelings (Free University of Brussels, Brussels, Belgium)
  • E. Mincsovics (Corvinus University of Budapest, Budapest, Hungary)
  • G. Morlock (Giessen University, Giessen, Germany)
  • A. Petruczynik (Medical University of Lublin, Lublin, Poland)
  • R. Skibiński (Medical University of Lublin, Lublin, Poland)
  • B. Spangenberg (Offenburg University of Applied Sciences, Germany)
  • T. Tuzimski (Medical University of Lublin, Lublin, Poland)
  • Y. Vander Heyden (Free University of Brussels, Brussels, Belgium)
  • A. Voelkel (Poznań University of Technology, Poznań, Poland)
  • B. Walczak (University of Silesia, Katowice, Poland)
  • W. Wasiak (Adam Mickiewicz University, Poznań, Poland)
  • I.G. Zenkevich (St. Petersburg State University, St. Petersburg, Russian Federation)

 

KOWALSKA, TERESA
E-mail: kowalska@us.edu.pl

SAJEWICZ, MIECZYSLAW
E-mail:msajewic@us.edu.pl

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2021  
Web of Science  
Total Cites
WoS
652
Journal Impact Factor 2,011
Rank by Impact Factor Chemistry, Analytical 66/87
Impact Factor
without
Journal Self Cites
1,789
5 Year
Impact Factor
1,350
Journal Citation Indicator 0,40
Rank by Journal Citation Indicator Chemistry, Analytical 72/99
Scimago  
Scimago
H-index
29
Scimago
Journal Rank
0,27
Scimago Quartile Score Chemistry (miscellaneous) (Q3)
Scopus  
Scopus
Cite Score
2,8
Scopus
CIte Score Rank
General Chemistry 210/409 (Q3)
Scopus
SNIP
0,586

2020
 
Total Cites
650
WoS
Journal
Impact Factor
1,639
Rank by
Chemistry, Analytical 71/83 (Q4)
Impact Factor
 
Impact Factor
1,412
without
Journal Self Cites
5 Year
1,301
Impact Factor
Journal
0,34
Citation Indicator
 
Rank by Journal
Chemistry, Analytical 75/93 (Q4)
Citation Indicator
 
Citable
45
Items
Total
43
Articles
Total
2
Reviews
Scimago
28
H-index
Scimago
0,316
Journal Rank
Scimago
Chemistry (miscellaneous) Q3
Quartile Score
 
Scopus
393/181=2,2
Scite Score
 
Scopus
General Chemistry 215/398 (Q3)
Scite Score Rank
 
Scopus
0,560
SNIP
 
Days from
58
submission
 
to acceptance
 
Days from
68
acceptance
 
to publication
 
Acceptance
51%
Rate

2019  
Total Cites
WoS
495
Impact Factor 1,418
Impact Factor
without
Journal Self Cites
1,374
5 Year
Impact Factor
0,936
Immediacy
Index
0,460
Citable
Items
50
Total
Articles
50
Total
Reviews
0
Cited
Half-Life
6,2
Citing
Half-Life
8,3
Eigenfactor
Score
0,00048
Article Influence
Score
0,164
% Articles
in
Citable Items
100,00
Normalized
Eigenfactor
0,05895
Average
IF
Percentile
20,349
Scimago
H-index
26
Scimago
Journal Rank
0,255
Scopus
Scite Score
226/167=1,4
Scopus
Scite Score Rank
Chemistry (miscellaneous) 240/398 (Q3)
Scopus
SNIP
0,494
Acceptance
Rate
41%

 

Acta Chromatographica
Publication Model Online only
Gold Open Access
Submission Fee none
Article Processing Charge 400 EUR/article
Regional discounts on country of the funding agency World Bank Lower-middle-income economies: 50%
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Acta Chromatographica
Language English
Size A4
Year of
Foundation
1992
Volumes
per Year
1
Issues
per Year
4
Founder Institute of Chemistry, University of Silesia
Founder's
Address
PL-40-007 Katowice, Poland, Bankowa 12
Publisher Akadémiai Kiadó
Publisher's
Address
H-1117 Budapest, Hungary 1516 Budapest, PO Box 245.
Responsible
Publisher
Chief Executive Officer, Akadémiai Kiadó
ISSN 2083-5736 (Online)

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