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1

Simultaneous determination of dantrolene with ibuprofen and diclofenac in plasma by HPLC-DAD: Application to comparative pharmacokinetic study

Abdel Moneim Mona M.

Acta Chromatographica

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2024

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Vol. 36, no. 1

23--30

EN

Muscle relaxants and pain killers with their different types are widely used as combination approach for treatment of pain associated with several muscle spasm conditions. A sensitive and simple HPLC-UV detection method was developed in this work for simultaneous assay of Dantrolene (DNT) and co-administrated: Ibuprofen (IBU) and Diclofenac (DIC). After simple protein precipitation, separation was achieved using C₁₈ column (150 × 4.6 mm) with a mobile phase of acidified water with orthophosphoric acid (pH = 3.5) and acetonitrile using gradient elution with a flow rate of 1 mL/min. The DAD was adjusted at 380, 219, 280 and 240 nm to measure DNT, IBU, DIC, and dexamethasone (internal standard), respectively. Linearity was demonstrated over the range from 0.1 to 3 μg/mL, 1 to 40 μg/mL, and 0.1 to 2 μg/mL for DNT, IBU, and DIC, respectively. The validated method was applied successfully to compare the effect of co-administration of IBU or DIC on the pharmacokinetic profile of DNT.

2

Validated UPLC-MS/MS method for the determination of ivosidenib in rat plasma: Application to a pharmacokinetic study

Chen Minle, Xu Jia, Chen Feifei, Zhou Quan, Wang Shuanghu, Han Aixia

Acta Chromatographica

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2023

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Vol. 35, no. 3

227--232

EN

Ivosidenib (AG-120) is an unlisted, but estimated to be valid, oral inhibitor for isocitrate dehydrogenase 1 (IDH1) in the phase Ⅰ study of IDH1-mutated acute myeloid leukemia (AML) patients. This paper presents the investigation and validation of a rapid, effective, qualitative and quantitative determination method of ivosidenib in rat plasma by ultra-performance liquid chromatography tandem mass spectrometry (UPLC-MS/MS). The samples were treated using acetonitrile precipitation to remove protein influence. Then, the supernatant was extracted to analyze plasma concentration traits. In the UPLC system, acetonitrile and water containing 0.1% formic acid were selected as a cosolvent mobile phase, applying a gradient elution to isolate compounds in a C18 column. Mass detections were performed on a triple quadruple mass spectrometer in positive ion mode. Electroshock characteristic fragment ionization was used for m/z 583.95→214.53 for ivosidenib for quantitative determination, m/z 583.95→186.6 for qualitative determination, and m/z 492.06→354.55 for IS. The selectivity, linearity, stability, accuracy and precision were verified by reaching the guideline criteria from European Medicine Agency (EMA) and the Food and Drug Administration (FDA). The calibration curve was linear over the concentration range of 2–2,000 ng mL⁻¹ for ivosidenib in rat plasma with a lower limit of quantification (LLOQ) of at least 2 ng mL⁻¹. Additionally, there was no distinct matrix effect or carry-over phenomenon. The method was successfully established and applied to separate ivosidenib from plasma, with the entire analytical process being performed within 3 min for each sample, which shows high-efficiency and convenience for further studies of ivosidenib.

3

Pharmacokinetics and bioavailability of curdione in mice by UPLC-MS/MS

Liang Qishun, Chen Tianyu, Luo Lvqi, Ma Yizhe, Wen Congcong, Huang Xueli

Acta Chromatographica

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2023

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Vol. 35, no. 2

144--148

EN

A UPLC-MS/MS method was developed to determinate curdione in the mouse blood, and the pharmacokinetics of curdione in mice after intravenous (5 mg kg⁻¹) and oral (20 mg kg⁻¹) administration were studied. The HSS T3 column was used for separation, and column temperature was set at 40 °C. Multiple reaction monitoring (MRM) mode were used for determination of curdione. Blood samples were taken from the caudal vein of Institute of Cancer Research (ICR) mice after administration of curdione. It showed a good linear relationship in the range of 1–500 ng mL⁻¹ (r > 0.998); the intra-day precision was <13%, the inter-day precision was <15%, and the accuracy was 90%–105%, the recovery was >77%, and the matrix effect was 97%–107%. The half-life was relatively short, and the bioavailability was 6.5%. The developed method was suitable for the pharmacokinetics of curdione in mice.

4

Determination of modafinil in rat plasma by UPLC-MS/MS and a study of its pharmacokinetics and bioavailability

He Yan, Ma Yizhe, Luo Lvqi, Chen Junying, Wen Congcong, Zhang Meiling

Acta Chromatographica

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2023

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Vol. 35, no. 2

187--192

EN

Modafinil has a strong and long-lasting awakening effect. Short-term use can improve cognitive and work efficiency. Therefore, it has been known to be abused by students and parents as a “smart drug.” It is in the first category of psychotropic drugs and strictly controlled. To detect modafinil in rat plasma and study the differences in the pharmacokinetics of modafinil between oral and sublingual administration in rats, an ultra-high performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS) method was developed. Rats were injected with modafinil by oral gavage and sublingual vein, respectively, blood was collected within a certain period, and the plasma was obtained by centrifugation. Midazolam was used as the internal standard, and the concentration of modafinil in the plasma was determined by UPLC-MS/MS, where a drug-time curve was created to calculate the pharmacokinetic parameters. The standard curve for modafinil ranged from 1 to 2000 ng mL⁻¹ with good linearity. The intra-day accuracy of modafinil was between 86% and 104%, and the intra-day accuracy was between 90% and 103%. Intra-day precision (RSD%) was less than 15%, inter-day precision (RSD%) was less than 15%. The matrix effect was between 93% and 102%, and the recovery was greater than 91%. The UPLC-MS/MS method established in this work has good selectivity and high sensitivity, and the UPLC-MS/MS method was successfully applied to the pharmacokinetics of modafinil by oral gavage and sublingual injection in rats. The bioavailability of modafinil was calculated to be 55.8%.

5

An UPLC-MS/MS method for quantification of spiraeoside in mouse blood and its application to a pharmacokinetic and bioavailability study

Cai Xiaojun, Dai Xiangyi, Li Zhou, Chen Junying, Wang Xianqin, Zhang Meiling

Acta Chromatographica

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2023

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Vol. 35, no. 3

272--277

EN

A simple, rapid, and sensitive method based on UPLC-MS/MS was developed to determine spiraeoside in mouse blood, and was applied to the pharmacokinetics and bioavailability of spiraeoside after mice after intravenous (a dose of 5 mg kg⁻¹) and oral (a dose of 20 mg kg⁻¹) administration. On HSS T3 column set at 40 °C, chromatographic separation was obtained with the mobile phase of acetonitrile and 0.1% formic acid using the gradient elution. Spiraeoside and internal standard (IS) were quantitatively analyzed using multiple reaction monitoring (MRM) mode in electrospray (ESI) positive interface. The MRM mode was monitoring the fragmentation of m/z 465.4→303.1 and m/z 451.3→ 289.2 for spironoside and IS, respectively. The results showed a good linear relationship was in the concentration range of 1–200 ng mL⁻¹ (r > 0.998) and the lower limit of quantification (LLOQ) was 1.0 ng mL⁻¹. The intra- and the inter-day precision (RSD%) of the method was within 14.0%, and the accuracy ranged from 90.0% to 115.0%. The extraction recovery of spriaeoside was better than 63.0%, and the matrix effects were in the range of 86%–98%. It also showed the half-life was short, and the absolute bioavailability was 4.0% in mice. Therefore, the established UPLC-MS/MS method was suitable for the pharmacokinetic and bioavailability study of spiraeoside in mice.

6

An improved ultra-high performance liquid chromatography-tandem mass spectrometry method determining hispidulin and homoplantaginin in rat plasma and associated pharmacokinetic studies

Zhang En, Chen Junying, Li Xia, Luo Lvqi, Ma Yizhe, Zhang Qingwei, Wang Xianqin

Acta Chromatographica

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2023

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Vol. 35, no. 4

331--337

EN

Flavonoids are the most abundant components in Salvia plebeia, with significant pharmacological antioxidant and hepatoprotective properties. Hispidulin and homoplantaginin are the main flavonoid components in S. Plebeia. In this study, we established an ultra-high performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS) to determine hispidulin and homoplantaginin in rat plasma samples, which were precipitated using acetonitrile-methanol (9:1, v/v). We used a UPLC HSS T3 (100 mm × 2.1 mm, 1.7 μm diameter) chromatographic column, an acetonitrile-water (containing 0.1% formic acid) mobile phase, and a gradient elution flow rate of 0.4 mL min⁻¹ in an elution time of 4 min. We used electrospray ionization (ESI) detection in positive ion mode, and multiple reaction monitoring mode (MRM) for quantitative analysis: m/z 301 → 286 for hispidulin, m/z 463 → 301 for homoplantaginin, and m/z 465 → 303 for internal standard (IS). In pharmacokinetic studies, 24 rats were orally administered hispidulin and homoplantaginin (5 mg kg⁻¹) and received sublingual intravenous injections (1 mg kg⁻¹) at two different doses, four groups with six rats/group. Differences in hispidulin and homoplantaginin pharmacokinetics in rat plasma were evaluated. The calibration curve showed good linearity in the 0.5–1,000 ng mL⁻¹ range, with r > 0.99. Precision, accuracy, recovery, matrix effects, and stability results all met standard biological sample detection requirements. Our pharmacokinetic studies showed hispidulin bioavailability was much higher than homoplantaginin at 17.8% and 0.1%, respectively.

7

Simultaneous determination of three naphthoquinones from Arnebia euchroma (Royle) Johnst in beagle plasma by UPLC-MS/MS and application for pharmacokinetics study

Wang Zhibin, Zhang Mingyu, Zhu Wenbo, Yang Chunjuan, Kuang Haixue

Acta Chromatographica

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2022

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Vol. 34, no. 4

403--411

EN

A rapid, simple and efficient ultra-performance liquid chromatography-electrospray ionization-tandem mass spectrometry (UPLC-ESI-MS/MS) method was established to simultaneous determination of shikonin, isobutyryl shikonin, β, βʹ-dimethylacryl alkanin in beagle plasma and evaluated by using esculetin as internal standard. The electrospray ionization (ESI) source was operated in negative ionization mode. Multi-reaction monitoring (MRM) was used to quantitatively analyzed shikonin m/z 287.0 → 217.9, isobutyryl shikonin m/z 357.0 → 268.9, β, βʹ-dimethylacryl alkanin m/z 370.0 → 270.1 and esculetin m/z 177.0 → 89.0, respectively. The method was validated for selectivity, linearity, lower limit of quantification, precision, accuracy, recovery, matrix effect and stability. All validation parameters met the acceptance criteria according to regulatory guidelines. This method was successfully applied for the pharmacokinetic study of shikonin, isobutyryl shikonin, β, βʹ-dimethylacryl alkanin in beagle dogs plasma after oral administration of A. euchroma extract.

8

Simultaneous determination of three active flavonoids in rat plasma by HPLC-MS/MS : application to a comparative pharmacokinetic investigation after oral administration of Schizonepeta tenuifolia aqueous extract with and without its volatile oil

Liu Siting, Jiang Yulan, Shan Mingqiu, Yu Sheng, Cheng Fangfang, Chen Peidong, Bao Beihua, Cao Yudan, Zhang Li, Wu Qinan

Acta Chromatographica

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2022

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Vol. 34, no. 1

32--40

EN

Schizonepeta tenuifolia Briq. (ST) has been used as an aromatic exterior-releasing medicine in clinical practice for thousands of years in China. Previous researches have revealed both volatile oil (STVO) and aqueous extract (STAE) from ST showed significant pharmacological activities, such as anti-virus, anti-inflammation, anti-oxidation, and immunoregulation. However, the influence between each other was still unknown. The purpose of this study was to compare the pharmacokinetic profiles of three main flavonoids (luteoloside, apigetrin, and hesperidin) in STAE to illustrate the influence of STVO. A liquid chromatography-tandem mass spectrometry (HPLC-MS) method was established to quantitatively analyze the three absorbed ingredients in the plasma of healthy rats. Biological samples were analyzed on an Agilent Eclipse Plus C18 column (3.0 mm × 150 mm, 3.5 μm) with gradient mobile phase (containing 0.2% formic acid and acetonitrile) at a flow rate of 0.8 mL/min. All the analytes and quercitrin (IS) were investigated with an electrospray ionization source (ESI) using multiple-reaction monitoring (MRM) in negative ionization mode. In addition, this quantitative method showed good linearities (r ≥ 0.9995) and the lower limits of quantification were 0.590–1.19 ng/mL. The intra- and inter-day precisions ranged 3.47–10.45% and 4.29–11.28% for the three analytes. The mean extraction recoveries were in the range of 77.41–109.79% and the average matrix effects were within 83.41–112.67%. The validated method has been fully applied to compare the pharmacokinetic parameters of the three flavonoid glycosides in rat plasma after oral administration of STAE and STAE+STVO. In comparison of luteoloside, apigetrin, and hesperidin in STAE group, it was found that different degree of increasing existed for the time to reach the maximum concentration (T max), elimination half-life time (T 1/2), the area under the concentration curves (AUC0→t and AUC0→∞) and the maximum concentrations (C max) in STAE+STVO group. As can be seen from above results, STVO could improve the absorption and bioavailability of the three analytes. These findings would provide some active and strong basis of safe clinical application for ST and further exploitation for STVO from the perspective of drug–drug interaction.

9

Simultaneous determination and pharmacokinetics studies of five isoflavones in rat plasma by UHPLC-MS/MS after oral administration of Radix Astragali extract

Han Jianwei, Zhu Wenbo, Yu Ling, Chen Yajun, Wu Gaosong, Wang Zhibin

Acta Chromatographica

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2022

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Vol. 34, no. 1

24--31

EN

A rapid, sensitive and convenient method based on ultra-high performance liquid chromatography tandem mass spectrometry (UHPLC-MS/MS) was developed and validated for the simultaneous quantification of calycosin-7-O-β-d-glucoside (CCSG), ononin, calycosin, (6aR,11aR)-9,10-dimethoxypterocarpan-3-O-β-d-glucopyanoside (DPPG), and 7,2′-dihydroxy-3′,4′-dimethoxyisoflavan-7-O-β-d-glucopyanoside (DIFG) in rat plasma after oral administration of the methanol extraction from Radix Astragali. Theophylline played the role of internal standard (IS). Preparation of plasma samples by liquid-liquid extraction method with ethyl acetate after precipitation of protein with methanol. The analytes were detected with a triple quadrupole tandem mass spectrometery (MS) in multiple reaction monitoring (MRM) mode and a positive ion electrospray ionization (ESI). The method was validated with the concentration ranges of 1.96–62.69 ng/mL for CCSG, 1.70–54.5 ng/mL for ononin, 1.85–59.06 ng/mL for calycosin, 2.14–137.24 ng/mL for DPPG and1.96–125.25 ng/mL for DIFG, respectively. The method had the lower limit of quantification (LLOQ) with 0.49, 0.21, 0.92, 1.07, and 0.98 ng/mL for CCSG, ononin, calycosin, DPPG and DIFG respectively, and the precision less than 10%. The RSD of the accuracy was in the range of −4.35–8.91%. The results may be helpful to provide more accurate references to clinical application of this herb.

10

Pharmacokinetics of tectorigenin, tectoridi, irigenin, and iridin in mouse blood after intravenous administration by UPLC-MS/MS

Li Jianbo, Yao Yuqi, Zhou Minyue, Yu Zheng, Jin Yinan, Wang Xianqin

Acta Chromatographica

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2022

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Vol. 34, no. 3

246--252

EN

Tectorigenin, tectoridin, irigenin, and iridin are the four most predominant compounds present in She Gan. She Gan has been used in traditional Chinese medicine because of its anti-inflammatory, hep- atoprotective, anti-tumor, antioxidant, phytoestrogen-like properties. In this paper, a UPLC-MS/MS method was developed to measure the pharmacokinetics of tectorigenin, tectoridin, irigenin, iridin after intravenous administration in mice. A UPLC BEH C18 (50 mm × 2.1 mm, 1.7 µm particle size) chromatographic column was utilized for separation of the four target analytes and internal standard (IS), and the analysis of blood plasma samples; the mobile phase consisted of an acetonitrile-water (w/0.1% formic acid) gradient elution. Electron spray ionization (ESI) positive-ion mode and multiple reaction monitoring (MRM) mode was used for quantitative analysis of the analytes and internal standard. The four compounds were administered intravenously (sublingual) at doses of 5 mg/kg. After blood sam- pling, samples were processed and then analyzed by UPLC-MS/MS. The linearity of the method was robust over the concentration range of 2-5,000 ng/mL. The intra-day precision of the analysis was within 15%, the inter-day precision was within 12%, and the accuracy was between 92% and 110%. The recoveries were 65–68%, and the matrix effect was 93-109%. The established UPLC-MS/MS detection method was then successfully applied to study the pharmacokinetics of tectorigenin, tectoridin, irigenin, iridin in mice.

11

Development of a rapid LC-MS/MS assay to determine letrozole in human plasma and its application in a pharmacokinetic study after oral administration

Li Pengfei, Zhang Xi, Wang Shumin, Wang Jing, Liu Ziqi, Wang Chen, Tong Weihang, Liu Lihong

Acta Chromatographica

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2022

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Vol. 34, no. 2

179--184

EN

Letrozole is one of the third generation aromatase inhibitors. It is suitable for the treatment of postmenopausal patients with advanced breast cancer and early treatment of breast cancer. It is necessary to develop a rapid, reliable, selective and sensitive LC–MS/MS assay to determine letrozole in human plasma to evaluate the clinical efficacy and adverse reactions with clinical pharmacokinetic and therapeutic drug monitoring. Separation was carried out on a Kromasil-C18 column using acetonitrile-water (55: 45, v/v) as mobile phase. Detection was carried out by multiple reaction monitoring on a 3200Qtrap mass spectrometry. The method needed one-step protein precipitation procedure only, and the cycle time was 2.5 min allowing 500–550 samples per day. It was linear within 0.30–50.00 ng/mL for plasma with the limit of detection (LOD) of 0.030 ng/mL. The intra- and inter-day RSD were 5.51–8.63%, 2.28–9.95% and the RE was 0.18–1.65%. The recovery rates of letrozole and internal standard for plasma were 89.30–98.55%. Letrozole was stable under all the conditions in the study. The method was sensitive enough to quantitate letrozole over a period of 288 h after giving a single oral dose of 2.5 mg–24 Chinese healthy volunteers. The absorption of letrozole was rapid with small individual difference, the tissue distribution of letrozole was more than that in blood, and the clearance was slow. Letrozole was similar to three-compartment model in vivo. Due to metabolism and excretion, the AUCs of letrozole varied greatly among individuals.

12

Determination of oroxin A, oroxin B, oroxylin A, oroxyloside, chrysin, chrysin 7-O-beta-gentiobioside, and guaijaverin in mouse blood by UPLC-MS/MS and its application to pharmacokinetics

Yu Zheng, Chen Fan, Jin Yinan, Zhou Minyue, Wang Xianqin, Shen Xiuwei

Acta Chromatographica

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2022

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Vol. 34, no. 4

394--402

EN

In this study, a UPLC-MS/MS method was developed to measure the concentrations of the flavonoids oroxin A, oroxin B, oroxylin A, oroxyloside, chrysin, chrysin 7-O-beta-gentiobioside, and guaijaverin in the blank mouse blood, and the method was then used in the measurement of the pharmacokinetics of the compounds in mice. Oroxin A, oroxin B, oroxylin A, oroxyloside, chrysin, chrysin 7-O-beta-gentiobioside, and guaijaverin were administered intravenously at a dose of 5 mg kg⁻¹, and the mouse blood (20 μL) was withdrawn from the caudal vein 0.08333, 0.25, 0.5, 1, 2, 4, 6, 8, and 10 h after administration. The mobile phase used for chromatographic separation by gradient elution was composed of acetonitrile and water (0.1% formic acid). The analytes were detected by operating in electrospray ionization (ESI) positive-ion mode using multiple reactions monitoring (MRM). The intra-day and inter-day accuracy ranged from 86.2 to 109.3%, the intra-day precision was less than 14%, and the inter-day precision was less than 15%. The matrix effect ranged from 85.3 to 111.3%, and the recovery of the analytes after protein precipitation were all above 78.2%. This method had the advantages of high sensitivity, accuracy, and recovery, and it had excellent selectivity, which enabled it to be applied to measuring the pharmacokinetics of the analytes in mice.

13

Comparative pharmacokinetic study of bicalutamide administration alone and in combination with vitamin D in rats

Shi Wenjing, Di Haixiao, Pang Bo, Jin Huixin, Liu Hongtao, Qiu Bo, Ren Bingnan, Pang Guoxun

Acta Chromatographica

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2022

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Vol. 34, no. 4

453--460

EN

Bicalutamide (BCL) has been approved for treatment of advanced prostate cancer (Pca), and vitamin D is inevitably used in combination with BCL in Pca patients for skeletal or anti-tumor strategies. Therefore, it is necessary to study the effect of vitamin D application on the pharmacokinetics of BCL. We developed and validated a specific, sensitive and rapid UHPLC–MS/MS method to investigate the pharmacokinetic behaviours of BCL in rat plasma with and without the combined use of vitamin D. Plasma samples were extracted by protein precipitation with ether/dichloromethane (2:1 v/v), and the analytes were separated by a Kinetex Biphenyl 100A column (2.1 × 100 mm, 2.6 μm) with a mobile phase composed of 0.5 mM ammonium acetate (PH 6.5) in water (A) and acetonitrile (B) in a ratio of A:B = 35:65 (v/v). Analysis of the ions was run in the multiple reactions monitoring (MRM) mode. The linear range of BCL was 5–2000 ng mL⁻¹. The intra- and inter-day precision were less than 14%, and the accuracy was in the range of 94.4–107.1%. The mean extraction recoveries, matrix effects and stabilities were acceptable for this method. The validated method was successfully applied to evaluate the pharmacokinetic behaviours of BCL in rat plasma. The results demonstrated that the pharmacokinetic property of BCL is significantly affected by combined use of vitamin D, which might help provide useful evidence for the clinical therapy and further pharmacokinetic study.

14

Simultaneous quantification of five bioactive 16-deoxybarringtogenol C triterpenoid saponins in rat plasma by HPLC-MS : application to a pharmacokinetic study after oral administration of Xanthoceras sorbifolia Bunge husks extract

Rong Weiwei, Sun Zheng, Guan Yina, Liu Ran, Li Qing, Bi Kaishun

Acta Chromatographica

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2021

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Vol. 33, no. 4

338--344

EN

In this study, a simple and rapid liquid chromatography-mass spectrometry method was developed to simultaneously determinate five 16-deoxybarringtogenol C triterpenoid saponins with the potential of neuroprotection in rat plasma following the oral administration of the Xanthoceras sorbifolia Bunge husks extract. With digoxin as the internal standard, the plasma samples were pre-treated by ethyl acetateisopropanol (1:1, v/v). The chromatographic separation of the five analytes was performed using a Phenomenex C18 column (250 mm 34.6 mm, 5.0 mm) with a mobile phase of 0.05% formic acid (A)acetonitrile (B). The mass spectrometric detection was carried out in the selected ion mode in positive ionization. The extraction recoveries of the five analytes were all over 71.28%. The established method was fully validated in line with the ICH and Food and Drug Administration (FDA) guidelines and successfully applied to the pharmacokinetic study on the five analytes in rat plasma. The terminal half-life (t1/2) of the five analytes was 2.92 ± 0.57, 5.52 ± 1.75, 2.48 ± 0.62, 2.95 ± 0.94, and 2.34 ± 0.81, respectively. This study was purposed to investigate the oral pharmacokinetic parameters and gain an in-depth insight into the reasonable preclinical use of the husks extract derived from X. sorbifolia Bunge.

15

Pharmacokinetics of palmatine in rat after oral and intravenous administration by UPLC-MS/MS

Li Jianbo, Hu Yujie, Wu Yajin, Feng Tiantian, Wen Congcong, Jiang Xiajuan

Acta Chromatographica

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2021

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Vol. 33, no. 1

25--29

EN

Palmatine is a compound with good water solubility extracted from Coptis chinensis, Fibraurea recisa Pierre, Cortex Phellodendri Chinensis. Palmatine has good antibacterial activity and mainly used for the treatment of bacterial dysentery, gynecological inflammation, surgical infection, and conjunctivitis. It has anti-diabetic, anti-oxidant, and cognitive-enhancing activities. In this study, we used UPLC-MS/MS to determinate palmatine in rat plasma, and investigated its pharmacokinetics. Coptisine was utilized as an internal standard (IS), and acetonitrile precipitation method was used to process the plasma samples. Chromatographic separation was achieved using a UPLC BEH C18 column using mobile phase of acetonitrile- 0.1% formic acid with gradient elution. Electrospray ionization (ESI) tandem mass spectrometry in multiple reaction monitoring (MRM) mode with positive ionization was applied. The results indicated that within the range of 1–500 ng/mL, linearity of palmatine in rat plasma was acceptable (r > 0.995), and the lower limit of quantification (LLOQ) was 1 ng/mL. Intra-day and inter-day precision RSD of palmatine in rat plasma were less than 14%. Accuracy range was between 93.7 and 107.1%, and matrix effect was between 101.6 and 109.4%. The method was successfully applied in the pharmacokinetics of palmatine in rats after oral and intravenous administration. The absolute bioavailability of the palmatine was 15.5% in rats.

16

Determination and pharmacokinetics of calycanthine in rat plasma by UPLC-MS/MS

Lu Meifei, Lu Xiaojie, Yu Zheng, Wen Congcong

Acta Chromatographica

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2021

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Vol. 33, no. 1

91--95

EN

Calycanthine is an important class of alkaloids extracted and isolated from the roots, leaves, flowers and fruits of Chimonanthus praecox. In this work, the UPLC-MS/MS method was used for determination of calycanthine in rat plasma, and the pharmacokinetics in rats were investigated. Midazolam was used as an internal standard (IS), and methanol precipitation method was used to pretreatment the rat plasma samples. Chromatographic separation was achieved on a UPLC BEH C18 (50 3 2.1 mm, 1.7 mm) column with the mobile phase of methanol- 0.1% formic acid aqueous solution with gradient elution. Multiple reaction monitoring (MRM) mode with positive ionization was applied for quantitative analysis, m/z 347.3 → 246.7 and 326.2 → 291.4 for calycanthine and IS, respectively. The results indicated that within the range of 1–200 ng/mL, linearity of calycanthine in rat plasma was good (r > 0.995), and the lower limit of quantification (LLOQ) was 1 ng/mL. Accuracy range was between 90.6 and 109.4%, precision (RSD) of calycanthine was less than 14%. The matrix effect was between 97.9% and 105.4%, the recovery was better than 85.6%. The developed UPLC-MS/MS method was successfully applied in the pharmacokinetics of calycanthine in rats after oral and intravenous administration. The absolute bioavailability of the calycanthine was 37.5% in rats.

17

CF–PK–PD analysis of natural hemostatic compounds from Toddalia asiatica (Linn) Lam root bark in rats

Zhang Xiaoyan, Liu Jie, Sun Wenbo, Shen Xiangchun, Gong Xiaojian, Wang Cong, Liang Yan, Zhou Wei

Acta Chromatographica

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2021

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Vol. 33, no. 3

261--269

EN

Natural hemostatic compounds from Toddalia asiatica (Linn) Lam (T. asiatica) root bark had been investigated by a novel strategy, chemical fingerprint–pharmacokinetic–pharmacodynamic (CF–PK–PD) for the first time in this study. The extract sample of T. asiatica root bark was subdivided into petroleum ether (PE), ethyl acetate (EA) and n-butanol (n-B) sample by reagent extraction, EA sample showed significant hemostatic activity using prothrombin time (PT), activated partial thromboplastin time (APTT) and fibrinogen (FIB) as evaluation indexes from rat plasma of PK experiment in hemorrhagic rat model. CF analysis was adopted to assist us to discover six natural compounds from T. asiatica root bark in actual rat plasma after sample treatment by Ultra Performance Liquid Chromatography-Electrospray Ionization (UPLC-ESI) MS, there were only lomatin and 5-methoxy-8-hydroxy psoralen showing significant hemostatic effect (P < 0.05) mainly through endogenous coagulation pathway and fibrinolytic system. In PK–PD study, six compounds in EA sample exhibited relatively rapid absorption and slow elimination characteristics. The mean Tmax and t1/2β of isopimpinellin and pimpinellin were 1.74 and 0.59 h, 5.31 and 6.89 h in rats. On the basis of Sigmoid–Emax model, PK–PD related curves of FIB in hemorrhagic rat model after treatment of T. asiatica root bark were obtained. Predicted Emax, EC50 and ke0 of FIB under isopimpinellin were 4.87 mg/mL, 1.39 μg/mL and 0.81 1/h; predicted Emax, EC50 and ke0 of FIB under pimpinellin were 4.29 mg/mL, 2.47 μg/mL and 0.77 1/h. In conclusion, hemostatic compounds from T. asiatica root bark had been materialized, there were lomatin, isopimpinellin, pimpinellin and 5-methoxy-8-hydroxy psoralen at least as its main active substances through coagulation pathways and fibrinolytic system. CF–PK–PD method as a promising method was worthy of follow-up opening, application in pharmaceutical research.

18

A rapid and sensitive High-Performance Liquid Chromatography-tandem Mass Spectrometry method for determining apremilast in beagle dog plasma and urine: Application in a pharmacokinetic study

Yan Genquan, Yu Lu, Chen Xu, Tran Triet, Nguyen Lam, Zhijun Wang, Wang Ling

Acta Chromatographica

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2021

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Vol. 33, no. 2

112--119

EN

A rapid and sensitive High-Performance Liquid Chromatography-tandem Mass Spectrometry (HPLC/MS/MS) method for determining apremilast in beagle dog plasma and urine samples was developed and validated using clopidogrel as the internal standard (IS). Apremilast was extracted from the plasma and urine samples by liquid–liquid extraction using methyl tert-butyl ether. Chromatographic separation was performed using a C8 column with gradient elution and a mobile phase containing methanol and 0.1% formic acid. Quantification was achieved in multiple reaction monitoring (MRM) mode with a transition of m/z 461.3→178.2 for apremilast and m/z 322.2→184.1 for clopidogrel (IS). This method was validated regarding its specificity, linearity, precision, accuracy, and stability. The lower limit of quantification (LLOQ) for this method was 5 ng/mL, and the calibration curve was linear over 5–1,000 ng/mL. The intra- and inter-run coefficients of variance (CV) of aprelimast in plasma samples were less than 12.92% and 10.64%, respectively, while in urine samples, the CV were less than 11.84% and 10.20%, respectively. The samples were stable under the tested conditions. This method was successfully applied to a pharmacokinetic study in beagle dogs following oral administration of 10 mg of apremilast.

19

Pharmacokinetics of isocorynoxeine in rat plasma after intraperitoneal administration by UPLC–MS/MS

Zhan Haichao, Wei Zhen, Ren Ke, Tong Shuhua, Wang Xianqin, Wu Qing

Acta Chromatographica

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2020

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Vol. 32, no. 4

260--263

EN

Isocorynoxeine is one of the main alkaloids in Chinese medicinal herbs, and has pharmacological activities such as antihypertensive, sedative, anticonvulsant, and neuronal protection. It is an effective component of Uncaria for the treatment of hypertension. In this study, we used a fast and sensitive ultra-performance liquid chromatography–tandem mass spectrometry (UPLC–MS/MS) to detect isocorynoxeine in rat plasma and investigated its pharmacokinetics in rats. Six rats were given isocorynoxeine (15 mg/kg) by intraperitoneal (i.p.) administration. Blood (100 μL) was withdrawn from the caudal vein at 5 and 30 min and 1, 2, 4, 6, 8, 12, and 24 h after administration. Chromatographic separation was achieved using a UPLC BEH C18 column using a mobile phase of acetonitrile–0.1% formic acid with gradient elution. Electrospray ionization (ESI) tandem mass spectrometry in the multiple reaction monitoring (MRM) mode with positive ionization was applied. Intra-day and inter-day precisions (relative standard deviation, %RSD) of isocorynoxeine in rat plasma were lower than 12%. The method was successfully applied in the pharmacokinetics of isocorynoxeine in rats after intraperitoneal administration. The t1/2 of isocorynoxeine is 4.9 ± 2.1 h, which indicates quick elimination.

20

Pharmacokinetics of ebeiedinone in mouse blood by UPLC–MS/MS

Jin Yongxi, Chen Yuyan, Liu Jiawen, Bao Xi, Zhi Yinghao, Wen Congcong, Zhu Wenzong

Acta Chromatographica

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2020

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Vol. 32, no. 3

194--198

EN

An ultra-performance liquid chromatography–tandem mass spectrometry (UPLC–MS/MS) method was established to determine ebeiedinone in mouse blood, and the pharmacokinetics of ebeiedinone after intravenous (0.5 mg/kg) and oral (2, 4, and 8 mg/kg) administration was studied. Twenty-four mice were randomly divided into 4 groups, 1 group was for intravenous administration (0.5 mg/kg), and other 3 groups were for oral administration (2, 4, and 8 mg/kg), with 6 rats in each group. Yubeinine was used as an internal standard. Multiple reaction monitoring (MRM) mode was used to quantitatively analyzed ebeiedinone m/z 414.4 → 91.1 and the internal standard m/z 430.4 → 412.3 in the electrospray ionization (ESI) positive interface. In the concentration range of 1–2000 ng/mL, the ebeiedinone in the mouse blood was linear (r2 > 0.995), and the lower limit of quantification was 1.0 ng/mL. In the mouse blood, the intra-day precision coefficient of variation (CV) was less than 15%, and the inter-day precision CV was less than 15%. The accuracy ranged from 85.4% to 114.6%, and the average recovery was higher than 61.3%. The matrix effect was between 87.0% and 106.5%. These data met the pharmacokinetic study requirements of ebeiedinone. The UPLC–MS/MS method was sensitive, rapid, and selective and was successfully applied to the pharmacokinetic study of ebeiedinone in mice. The absolute bioavailability of ebeiedinone was 30.6%.