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1.
    
A simple and sensitive liquid chromatography tandem mass spectrometry method was validated for simultaneous quantification of evodiamine and its metabolites 10‐hydroxyevodiamine (M1), 18‐hydroxyevodiamine (M2), 10‐hydroxyevodiamine‐glucuronide (M3) and 18‐hydroxy‐ evodiamine‐glucuronide (M4) in rat plasma for the first time. The analytes were extracted with acetonitrile and separated on a C18 column within 3 min. The detection was achieved in positive selected reaction monitoring mode with precursor‐to‐product transitions at m/z 304.1 → 161.1 for evodiamine, m/z 320.1 → 134.1 for M1, m/z 320.1 → 150.1 for M2, m/z 496.2 → 134.1 for M3, m/z 496.2 → 171.1 for M4 and m/z 349.2 → 305.1 for camptothecin (internal standard). The linearity was evident over the tested concentration ranges with correlation coefficients >0.9991. The lower limits of quantification for evodiamine, M1, M2, M3 and M4 were 0.1, 0.1, 0.1, 0.25 and 0.25 ng mL−1, respectively. Extraction recoveries and matrix effects of the analytes were within the ranges of 84.51–97.21 and 90.13–103.30%, respectively. The accuracy (relative error) ranged from −8.14 to 7.23% while the intra‐ and inter‐day precisions (relative standard deviation) were < 9.31%. The validated assay was successfully applied for the pharmacokinetic study of evodiamine, M1, M2, M3 and M4 in rat. The current study will be helpful in understanding the in vivo disposition of evodiamine.  相似文献   

2.
    
A rapid, sensitive and reproducible LC–MS/MS method was developed and validated to determine iguratimod in human plasma. Sample preparation was achieved by protein precipitation with acetonitrile. Chromatographic separation was operated on an Ultimate® XB‐C18 column (2.1 × 50 mm, 3.5 μm, Welch) with a flow rate of 0.400 mL/min, using a gradient elution with acetonitrile and water which contained 2 mm ammonium acetate and 0.1% formic acid as the mobile phase. The detection was performed on a Triple Quad™ 5500 mass spectrometer coupled with an electrospray ionization interface under positive‐ion multiple reaction monitoring mode with the transition ion pairs of m/z 375.2 → 347.1 for iguratimod and m/z 244.3 → 185.0 for agomelatine (the internal standard), respectively. The method was linear over the range of 5.00–1500 ng/mL with correlation coefficients ≥0.9978. The accuracy and precision of intra‐ and inter‐day, dilution accuracy, recovery and stability of the method were all within the acceptable limits and no matrix effect or carryover was observed. As a result, the main pharmacokinetic parameters of iguratimod were as follows: Cmax, 1074 ± 373 ng/mL; AUC0–72, 13591 ± 4557 ng h/mL; AUC0–∞, 13,712 ± 4613 ng h/mL; Tmax, 3.29 ± 1.23 h; and t1/2, 8.89 ± 1.23 h.  相似文献   

3.
    
A simple and reliable liquid chromatography–mass spectrometry (LC–MS) method was developed for simultaneous determination of saikosaponin A, saikosaponin B1, saikosaponin C, saikosaponin D and saikosaponin F in rat plasma using glycyrrhetinic acid as an internal standard (IS). The separation was operated on a Waters BEH C18 column. The mobile phases of gradient elution consisted of acetonitrile (A) and 0.1% aqueous acetic acid (B). The mass spectrometric detection was accomplished in multiple reaction monitoring mode. The five saponins displayed good linearity (r2 > 0.9996). The lower limits of quantitation of saikosaponin A, saikosaponin B1, saikosaponin C, saikosaponin D and saikosaponin F were determined to be 2.9, 2.3, 3.5, 2.9 and 3.1 ng/mL, respectively. Moreover, the intra‐ and inter‐day precisions of the five saponins showed an RSD within 2.96%, whereas the accuracy (RE) ranged from ?2.28 to 2.78%. Finally, the developed method was fully validated and applied to a comparative pharmacokinetic study of the five bioactive saponins in rats following oral administration of crude and vinegar‐processed Bupleurum scorzonerifolium.  相似文献   

4.
    
An accurate and sensitive LC–MS/MS method for determining thalidomide, 5‐hydroxy thalidomide and 5′‐hydroxy thalidomide in human plasma was developed and validated using umbelliferone as an internal standard. The analytes were extracted from plasma (100 μL) by liquid–liquid extraction with ethyl acetate and then separated on a BETASIL C18 column (4.6 × 150 mm, 5 μm) with mobile phase composed of methanol–water containing 0.1% formic acid (70:30, v/v) in isocratic mode at a flow rate of 0.5 mL/min. The detection was performed using an API triple quadrupole mass spectrometer in atmospheric pressure chemical ionization mode. The precursor‐to‐product ion transitions m/z 259.1 → 186.1 for thalidomide, m/z 273.2 → 161.3 for 5‐hydroxy thalidomide, m/z 273.2 → 146.1 for 5′‐hydroxy thalidomide and m/z 163.1 → 107.1 for umbelliferone (internal standard, IS) were used for quantification. The calibration curves were obtained in the concentrations of 10.0–2000.0 ng/mL for thalidomide, 0.2–50.0 ng/mL for 5‐hydroxy thalidomide and 1.0–200.0 ng/mL for 5′‐hydroxy thalidomide. The method was validated with respect to linear, within‐ and between‐batch precision and accuracy, extraction recovery, matrix effect and stability. Then it was successfully applied to estimate the concentration of thalidomide, 5‐hydroxy thalidomide and 5′‐hydroxy thalidomide in plasma samples collected from Crohn's disease patients after a single oral administration of thalidomide 100 mg.  相似文献   

5.
    
Triptolide is one of the main active ingredients of Tripterygium wilfordii Hook. F. In this study, a sensitive LC–MS/MS method was established and validated to determine the concentration of triptolide in rat plasma. Triptolide and an internal standard [(5R)‐5‐hydroxytriptolide] were extracted from 100 μL of rat plasma with acetonitrile, and the dried residue was then reconstituted and reacted with benzylamine to produce benzylamine triptolide and benzylamine (5R)‐5‐hydroxytriptolide. Derivatization increased the sensitivity of triptolide detection by ~100‐fold. Quantification was performed using a QTRAP 5500 tandem mass spectrometer with positive electrospray ionization in multiple reaction monitoring mode with an ion transition m/z 468.5 → 192.0 for benzylamine triptolide and m/z 484.3 → 192.1 for benzylamine (5R)‐5‐hydroxytriptolide. Good linearity was observed in the range of 0.030–100 ng/mL with a lower limit of quantitation of 0.030 ng/mL. The intra‐ and inter‐day precision was <6.5%, and the accuracy ranged from ?11.7 to ?4.4%. The recovery remained consistent and was reproducible at different concentrations. This method was successfully applied to the study of triptolide drug–drug interactions in Sprague–Dawley rats. With the use of itraconazole (40 mg/kg, p.o.) as a CYP3A inhibitor, the plasma exposure of triptolide in rats was increased by 36%.  相似文献   

6.
    
Opportunistic fungal infections are common in immunocompromised cancer patients, especially patients undergoing chemotherapy. Because antitumor agents are possible to combine with antifungal agents in clinical, it is necessary to study drug–drug interaction between antitumor agents and antifungal agents. The aim of the study was to explore a method for the simultaneous determination of voriconazole and docetaxel in plasma and investigate pharmacokinetic interaction of voriconazole and docetaxel in rats. A precise and reliable method using liquid chromatography tandem mass spectrometry (LC–MS/MS) was established for the simultaneous measure of docetaxel and voriconazole in rat plasma after liquid–liquid extraction with ethyl acetate. The method was fully validated and successfully applied to a pharmacokinetic interaction study of docetaxel and voriconazole in rats after single or combined administration. We found that the AUC of each drug after coadministration increased compared with that after the single administration, which might be caused by interaction at the absorption stage or the competitive inhibition on the metabolic enzymes. This established method can be utilized to study the detailed mechanism of the drug–drug interaction and guide rational drug use in the clinic.  相似文献   

7.
    
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8.
Nitazoxanide (NTZ) is a broad‐spectrum antimicrobial agent. Tizoxanide (T) and tizoxanide glucuronide (TG) are the major circulating metabolites after oral administration of NTZ. A rapid and specific LC–MS/MS method for the simultaneous quantification of T and TG in mouse plasma was developed and validated. A simple acetonitrile‐induced protein precipitation method was employed to extract two analytes and the internal standard glipizide from 50 μL of mouse plasma. The purified samples were resolved using a C18 column with a mobile phase consisting of acetonitrile and 5 mm ammonium formate buffer (containing 0.05% formic acid) following a gradient elution. An API 3000 triple quadrupole mass spectrometer was operated under multiple reaction‐monitoring mode with electrospray ionization. The precursor‐to‐product ion transitions m/z 264 → m/z 217 for T and m/z 440 → m/z 264 for TG were used for quantification. The developed method was linear in the concentration ranges of 1.0–500.0 ng/mL for T and 5.0–1000.0 ng/mL for TG. The intra‐ and inter‐day precision and accuracy of the quality control samples at low, medium and high concentrations exhibited an RSD of <13.2% and the accuracy values ranged from ?9.6 to 9.3%. We used this validated method to study the pharmacokinetics of T and TG in mice following oral administration of NTZ. Copyright © 2016 John Wiley & Sons, Ltd.  相似文献   

9.
    
Hinokiflavone has drawn a lot of attention for its multiple biological activities. In this study, a sensitive and selective method for determination of hinokiflavone in rat plasma was developed for the first time, using liquid chromatography–tandem mass spectrometry (LC–MS/MS). Amentoflavone was used as an internal standard. Separation was achieved on a Hypersil Gold C18 column with isocratic elution using methanol–water (65:35, v /v) as mobile phase at a flow rate of 0.3 mL/min. A triple quadrupole mass spectrometer operating in the negative electrospray mode with selected reaction monitoring was used to detect the transitions of m/z 537 → 284 for hinokiflavone and m/z 537 → 375 for IS. The LOQ was 0.9 ng/mL with a linear range of 0.9–1000 ng/mL. The intra‐ and inter‐day accuracy (RE%) ranged from −3.75 to 6.91% and from −9.20 to 2.51% and the intra‐ and inter‐day precision (RSD) was between 0.32–14.11 and 2.85–10.04%. The validated assay was successfully applied to a pharmacokinetic study of hinokiflavone in rats. The half‐life of drug elimination at the terminal phase was 6.10 ± 1.86 h, and the area under the plasma concentration‐time curve from time zero to the time of last measurable concentration and to infinity values obtained were 2394.42 ± 466.86 and 2541.93 ± 529.85 h ng/mL, respectively.  相似文献   

10.
A sensitive and selective liquid chromatography–tandem mass spectrometry method for the determination of piracetam in rat plasma was developed and validated over the concentration range of 0.1–20 µg/mL. After addition of oxiracetam as internal standard, a simplified protein precipitation with trichloroacetic acid (5%) was employed for the sample preparation. Chromatographic separation was performed by a Zorbax SB‐Aq column (150 × 2.1 mm, 3.5 µm). The mobile phase was acetonitrile–1% formic acid in water (10:90 v/v) delivered at a flow rate of 0.3 mL/min. The MS data acquisition was accomplished in multiple reaction monitoring mode with a positive electrospray ionization interface. The lower limit of quantification was 0.1 µg/mL. For inter‐day and intra‐day tests, the precision (RSD) for the entire validation was less than 9%, and the accuracy was within the 94.6–103.2% range. The developed method was successfully applied to pharmacokinetic studies of piracetam in rats following single oral administration dose of 50 mg/kg. Copyright © 2010 John Wiley & Sons, Ltd.  相似文献   

11.
    
Bicyclol is a synthetic drug widely used to treat chronic hepatitis B. This study aimed to develop a selective, sensitive and high‐throughput liquid chromatography–tandem mass spectrometric method for the detection of bicyclol in human plasma. Bicyclol was detected using a multiple reaction monitoring mode, with ammonium adduct ions (m/z 408.2) as the precursor ion and the [M‐CH3]+ ion (m/z 373.1) subjected to demethylation as the product ion. Chromatographic separation was achieved using a Zobax Eclipse XDB‐C18 column with a gradient elution and a mobile phase of 2 mm ammonium formate and acetonitrile. Bicyclol was extracted from plasma matrix by precipitation. A linear detection response was obtained for bicyclol ranging from 0.500 to 240 ng/mL, and the lower limit of quantification was 0.500 ng/mL. The intra‐ and inter‐day precisions were all ≤7.4%, and the accuracies were within ±6.0%. The extraction recovery was >95.9%, and the matrix effects were between 96.0% and 108%. Bicyclol was found to be unstable in human plasma at room temperature, but the degradation was minimized by conducting sample collection and preparation in an ice bath. The validated method was successfully applied to investigate the pharmacokinetics of bicyclol tablets in six healthy Chinese volunteers.  相似文献   

12.
    
This study aims to develop and validate a simple and sensitive liquid chromatography with tandem mass spectrometry (LC–MS/MS) method for investigating the pharmacokinetic characteristics of bavachalcone. Liquid–liquid extraction was used to prepare plasma sample. Chromatographic separation of bavachalcone and IS was achieved using a Venusil ASB C18 (2.1 × 50 mm, 5 μm) column with a mobile phase of methanol (A)–water (B) (70:30, v /v). The detection and quantification of analytes was performed in selected‐reaction monitoring mode using precursor → product ion combinations of m/z 323.1 → 203.2 for bavachalcone, and m/z 373.0 → 179.0 for IS. Linear calibration plots were achieved in the range of 1–1000 ng/mL for bavachalcone (r 2 > 0.99) in rat plasma. The recovery of bavachalcone ranged from 84.1 to 87.0%. The method was precise, accurate and reliable. It was fully validated and successfully applied to pharmacokinetic study of bavachalcone.  相似文献   

13.
    
Several chemical and biological studies have revealed R,S‐goitrin as the main bioactive constituent of Isatis indigotica Fort., responsible for antiviral antiendotoxin activity; however, few pharmacokinetic studies have been conducted. To comprehend the kinetics of R,S‐goitrin and promote its curative application, a rapid and sensitive UHPLC–MS/MS method was developed. The selected reaction monitoring transitions were m/z 130.0 → 70.0 for R,S‐goitrin and m/z 181.1 → 124.0 for the internal standard in a positive‐ion mode. The established UHPLC–MS/MS method achieved good linearity for R,S‐goitrin at 10–2000 ng/mL. The intra‐ and interday accuracy levels were within ±9.7%, whereas the intraday and interday precision levels were <11.3%. The extraction recovery, stability and matrix effect were within acceptable limits. The validated method was successfully applied for the pharmacokinetic analysis of R,S‐goitrin in rats after oral administration. Moreover, a total of six metabolites were structurally identified through UHPLC–Q/TOF–MS. The proposed metabolic pathways of R,S‐goitrin in rats involve demethylation, acetylation, glutathionylation and oxygenation.  相似文献   

14.
    
A simple and sensitive liquid chromatography tandem mass spectrometry (LC–MS/MS) method was developed for the simultaneous determination of isoquercitrin, kaempferol‐3‐O‐rutinoside and tiliroside in rat plasma. Plasma samples were deproteinized with methanol and separated on a Hypersil Gold C18 column (2.1 × 50 mm, i.d., 3.0 μm) using gradient elution with the mobile phase of water and methanol at a flow rate of 0.4 mL/min. Mass spectrometric detection was performed with negative ion electrospray ionization in selected reaction monitoring mode. All analytes showed good linearity over their investigated concentration ranges (r2 > 0.99). The lower limit of quantification was 1.0 ng/mL for isoquercitrin and 2.0 ng/mL for kaempferol‐3‐O‐rutinoside and tiliroside, respectively. Intra‐ and inter‐day precisions were <8.2% and accuracy ranged from −11.5 to 9.7%. The mean extraction recoveries of analytes and IS from rat plasma were >80.4%. The assay was successfully applied to investigate the pharmacokinetic study of the three ingredients after oral administration of Rubus chingii Hu to rats.  相似文献   

15.
    
Genipin (GP), an active metabolite of geniposide (GE), exhibits more potent pharmacological effects than its parent compound. In this paper, a sensitive LC‐MS/MS method was developed and fully validated for the simultaneous determination of GE and GP in rat plasma. We found that GP degraded rapidly in rat plasma at room temperature as a result of irreversible binding with the endogenous nucleophiles in plasma. GP was stable when the sample's pH was ≤4.0. The degradation of GP in rat plasma was well prevented by immediate addition of 5% glacial acetic acid to the freshly collected plasma. The detection was performed on a tandem mass spectrometer coupled with electrospray ionization source in negative mode. Quantification was conducted by multiple reaction monitoring of the transitions [M + CH3COO]− m/z 447.3 → 225.3 for GE and [M − H]− m/z 225.2 → 123.1 for GP. The method exhibited high sensitivity (LLOQ 1 ng/mL for GE and 0.2 ng/mL for GP) by selecting the acetate adduct ions as the precursor ions for GE. The robust developed method was successfully applied to a pharmacokinetic study in rats after oral administration of GE.  相似文献   

16.
    
Lansoprazole (LPZ) is a commercially available proton‐pump inhibitor whose primary metabolite, lansoprazole sulfide (LPZS) was recently reported to have in vitro and in vivo activity against Mycobacterium tuberculosis . It was also reported that a 300 mg kg−1 oral administration of LPZS was necessary to reach therapeutic levels in the lung, with the equivalent human dose being unrealistic. A validated liquid chromatography–tandem mass spectrometric method (LC–MS/MS) for the simultaneous quantification LPZ and LPZS in rat plasma and lung homogenates was developed. We administered 15 mg kg−1 oral doses of LPZ to a healthy rat model to determine the pharmacokinetics of its active metabolite, LPZS, in plasma and lung tissue. We found that the LPZS was present in amounts that were below the limit of quantification. This prompted us to administer the same dose of LPZS to the experimental animals intraperitoneally (i.p.). Using this approach, we found high concentrations of LPZS in plasma and lung, 7841.1 and 9761.2 ng mL−1, respectively, which were significantly greater than the minimum inhibitory concentration (MIC) for Mycobacterium tuberculosis. While oral and i.p. administration of LPZ resulted in significant concentrations in the lung, it did not undergo sufficient cellular conversion to its anti‐TB metabolite. However, when LPZS itself was administered i.p., significant amounts penetrated the tissue. These results have implications for future in vivo studies exploring the potential of LPZS as an anti‐TB compound.  相似文献   

17.
    
TAK‐875 is a selective partial agonist of human GPR40 receptor, which was unexpectedly terminated at phase III clinical trials owing to its severe hepatotoxicity. The purpose of this study was to investigate the pharmacokinetics of TAK‐875 and its toxic metabolite TAK‐875‐acylglucuronide in rat plasma by liquid chromatography tandem mass spectrometry (LC–MS/MS). Plasma samples were extracted with ethyl acetate and chromatographic separations were achieved on a C18 column with water and acetonitrile containing 0.05% ammonium hydroxide as mobile phase. The sample was detected in selected reaction monitoring mode with precursor‐to‐product ion transitions being m/z 523.2 → 148.1, m/z 699.3 → 113.1 and m/z 425.2 → 113.1 for TAK‐875, TAK‐875‐acylglucuronide and IS, respectively. The assay showed good linearity over the tested concentration ranges (r > 0.9993), with the LLOQ being 0.5 ng/mL for both analytes. The extraction recovery was >78.45% and no obvious matrix effect was detected. The highly sensitive LC–MS/MS method has been further applied for the pharmacokinetic study of TAK‐875 and its toxic metabolite TAK‐875‐acylglucuronide in rat plasma. Pharmacokinetics results revealed that oral bioavailability of TAK‐875 was 86.85%. The in vivo exposures of TAK‐875‐acylglucuronide in terms of AUC0–t were 17.54 and 22.29% of that of TAK‐875 after intravenous and oral administration, respectively.  相似文献   

18.
    
Ginsenoside Rk1 (Rk1) exhibited various potent biological activities. However, its pharmacokinetic profile in vivo remains unclear. In the present study, a simple and sensitive liquid chromatography tandem mass spectrometry method was developed and validated for determination of Rk1 in rat plasma and applied in a pharmacokinetic study. The sample was precipitated with acetonitrile and separated on a Zorbax Eclipse XDB C18 column (50 × 2.1 mm, 1.8 μm). The mobile phase was composed of 0.1% formic acid in water and acetonitrile at a flow rate of 0.4 mL/min. Rk1 and internal standard (ginsenoside Rg3) were quantitatively monitored with precursor‐to‐product ion transitions of m/z 765.4 → 441.5 and m/z 783.5 → 621.4, respectively. The assay was linear over the concentration range of 5–1000 ng/mL (r > 0.99) with the LLOQ of 5 ng/mL. Other parameters including intra‐ and inter‐day precision and accuracy, extraction recovery and matrix effect were within the acceptable limits. The analyte was stable under the tested storage conditions. The validated method has been successfully applied to a pharmacokinetic study of Rk1 in rat plasma after intravenous (5 mg/kg) and oral (25 mg/kg, 50 mg/kg) administration. After oral administration, Rk1 could be detected in blood at 30 min and reached the highest concentration at 4.29~4.57 h. Our results demonstrated that Rk1 showed low clearance, moderate half‐life (3.09–3.40 h) and low bioavailability (2.87–4.23%). The study will provide information for the further application of Rk1.  相似文献   

19.
Silodosin (SLD) is a novel α1‐adrenoceptor antagonist which has shown promising clinical efficacy and safety in patients with benign prostatic hyperplasia (BPH). However, lack of information about metabolism of SLD prompted us to investigate metabolic fate of SLD in rats. To identify in vivo metabolites of SLD, urine, feces and plasma were collected from Sprague–Dawley rats after its oral administration. The samples were prepared using an optimized sample preparation approach involving protein precipitation followed by solid‐phase extraction and then subjected to LC/HR‐MS/MS analysis. A total of 13 phase I and six phase II metabolites of SLD have been identified in rat urine which includes hydroxylated, N‐dealkylated, dehydrogenated, oxidative, glucosylated, glucuronide and N‐sulphated metabolites, which are also observed in feces. In plasma, only dehydrogenated, N‐dealkylated and unchanged SLD are observed. The structure elucidation of metabolites was done by fragmentation in MS/MS in combination with HRMS data. The potential toxicity profile of SLD and its metabolites were predicted using TOPKAT software and most of the metabolites were proposed to show a certain degree of skin sensitization and occular irritancy. Copyright © 2016 John Wiley & Sons, Ltd.  相似文献   

20.
A rapid and sensitive liquid chromatography tandem mass spectrometry quantitative analysis method was established for the pharmacokinetics and tissue distribution study of physalin B in rat. Physalin B and physalin H (internal standard, IS) were separated on an Agilent Eclips XDB C8 column. MS detection was performed on a triple quadrupole tandem mass spectrometer in the multiple reaction monitoring mode with a positive eletrospray ionization source. The assay was validated in the concentration ranges of 22.6–22600 ng/mL for heart and lung and 4.52–4520 ng/mL for other tissues. The intra‐ and inter‐day precisions (RSD) were ≤9.23 and ≤12.51%, respectively, with accuracy (%) in the range of 88.07–113.2%. A pharmacokinetic study showed that physalin B has a long dwell time with a half‐life of 321.2 ± 29.5 min and clearance of 175.4 ± 25.7 mL/min/kg after intravenous administration. Additionally, physalin B showed a wide tissue distribution with a special higher penetration in lung. The data presented in this study could provide useful information for the further study of physalin B. Copyright © 2016 John Wiley & Sons, Ltd.  相似文献   

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