查看更多>>摘要：Abstract The presence of azithromycin in the human plasma of pediatric patients was determined with a UHPLC‐MS/MS assay. Sample preparation was done by protein precipitation, and the separation was achieved on a C18 column by the gradient mixture of the mobile phase A (0.1% acetic acid and 3?mM ammonium acetate in water) and the mobile phase B (0.1% acetic acid and 3?mM ammonium acetate in the solution of acetonitrile, methanol, and water, 47.5/47.5/5, V/V/V). The multiple reaction monitoring mode was adopted to monitor the precursor‐to‐product ion transitions of m/z 749.6?→?m/z 591.5 for azithromycin and m/z 753.6?→?m/z 595.5 for azithromycin‐13C‐d3 (the internal standard) at the positive ionization mode. The calibration curve ranged from 0.5 to 500.0?ng·mL?1, and the correlation coefficient was greater than 0.99. The intra‐ and inter‐batch precision was less than 13.7%. Accuracy determined at four concentrations ranged from 99.5 to 110.8%. The extraction recoveries were more than 95%, and the matrix effects were 98–100%. The stability under various conditions was acceptable with the accuracy deviation within 9.2%. In conclusion, our method was simple, sensitive, and reliable for quantifying azithromycin in plasma among pediatric patients.
查看更多>>摘要：Abstract Ethanol intake can alter pharmacokinetics by increasing the solubility or enhancing the absorption of concomitant drugs. Here, a selective, sensitive and reproducible high‐performance liquid chromatography–tandem mass spectrometry method for the quantitative analysis of nicardipine in rat plasma was developed using simple protein precipitation. The calibration curve was linear over a concentration range of 1–2,000?ng/ml (r2?>?0.998). Accuracy ranged from 93.4 to 112.2% and precision was within 12.1% from three independent analytical batches. Stable conditions for the quantification of nicardipine in rat plasma were established in various conditions, including sample storage and handling. The matrix effect was negligible, and recovery was consistent at three different levels of quality control sample. The method was applied to assessment for the effect of ethanol on the pharmacokinetics of nicardipine in rats. The oral bioavailability of nicardipine was increased from 5.4 to 9.4% in Sprague–Dawley rats by concomitant oral administration of ethanol whereas the half‐life was not altered. The findings indicated that concomitant ethanol intake can increase systemic drug exposure by increasing gastrointestinal absorption, especially poorly soluble drugs. This study provides an insight for further investigation of the alteration of the pharmacological effect of poorly soluble drugs owing to ethanol intake.
查看更多>>摘要：Abstract Docetaxel is one of the clinical first‐line drugs and its combination with other chemotherapy agents for advanced or metastatic cancers has attracted widespread attention. Therefore, to promote the clinical application of docetaxel alone or in combination, a comprehensive investigation of the metabolic mechanism of docetaxel is of great importance. Here, we apply an integrative analysis of metabolomics and network pharmacology to elucidate the underlying mechanisms of docetaxel. After taking the intersection of the aforesaid two methods, five pathways including ABC (ATP‐binding cassette) transporters, central carbon metabolism in cancer, glycolysis and gluconeogenesis, cysteine and methionine metabolism, and arginine biosynthesis have been screened. Concerning the interaction network of these pathways and the anti‐apoptosis effect of docetaxel itself, the central carbon metabolism in cancer pathway was mainly focused on. This study may help delineate global landscapes of cellular protein–metabolite interactions, to provide molecular insights about their mechanisms of action as well as to promote their clinical applications.
查看更多>>摘要：Abstract Passive permeability is one of the key features that determine absorbability and one of the most studied properties in the early phases of drug development. Newly synthesized succinimide derivatives from two different series (1‐aryl‐3‐methylsuccinimides and 1‐aryl‐3‐ethyl‐3‐methylsuccinimides) with high biological potential have been subjected to estimation of their passive permeability and their association with (a) experimentally obtained anisotropic lipophilicity, (b) in silico–calculated lipophilicity and (c) in silico–predicted permeability and absorbability. Non‐cellular‐based parallel artificial membrane permeability assay was applied for quantifying their passive permeation, expressed as logPapp. Passive permeation was governed by the lipophilicity of the analysed compounds, and anisotropic lipophilicity was related with statistically significant passive transcellular diffusion (r2?=?0.614, P?<?0.001). Moreover, experimentally determined passive permeability, logPapp, was statistically significantly associated with both in silico–predicted absorption constant, ka (r2?=?0.7886, P?<?0.001), and human intestinal absorption (HIA) in percentage (r2?=?0.484, P?<?0.001), respectively. However, there was no statistically significant relationship between experimentally obtained permeability on non‐cellular‐based model and in silico–predicted Caco‐2 permeability based on the predictions conducted on two different software. Based on the obtained results, anisotropic systems are promising surrogates for determining lipophilicity, except for compounds with acidic functional groups that are completely ionized under (pH?=?7.4).
查看更多>>摘要：Abstract The current aim of this study is to develop a simple, sensitive, and robust analytical method that can separate the Rivaroxaban and its related impurities by using HPLC. This new method can separate enantiomers and all the process‐related impurities of rivaroxaban. This method can also be used to determine the assay of rivaroxaban in drug substances and drug products. This new method was developed using a Chiralpak IC (250?×?4.6?mm, 5?μm) column at 27°C with a gradient program of 25.0?min at a flow rate of 0.8?mL/min. Mobile phase A consisted of acetonitrile, ethanol, and n‐butyl amine in the ratio of 95:5:0.5 (v/v/v), respectively. Mobile phase B consisted of a mixture of Milli‐Q water, methanol, and n‐butyl amine in the ratio of 50:50:0.5 (v/v/v), respectively. The detector wavelength was 254?nm. Rivaroxaban was subjected to the forced degradation conditions (stress conditions) of hydrolysis, base, acid, thermal, photolysis, and oxidation. The degradation products were well separated from rivaroxaban peak and enantiomer peak, and its potential impurities prove the stability‐indicating power of the method. The proposed new stability‐indicating method was validated with respect to specificity, precision, accuracy, limit of quantification, limit of detection, linearity robustness, and roundness per International Conference on Harmonization guidelines. The %RSD (relative standard deviation) for six sample preparations for rivaroxaban and impurities less than 10% and the recovery is between 90 and 110%. The current method can be used in quality control labs for analysis of commercial products.
查看更多>>摘要：Abstract This study developed a UPLC–MS/MS method to detect isoscoparin in mouse blood, determined the pharmacokinetics of isoscoparin in mice after intravenous (5?mg/kg) and intragastric (20?mg/kg) administration, and calculated the absolute bioavailability. A HSS T3 column was used for separation, and the column temperature was set at 40°C. The mobile phases were acetonitrile and 0.1% formic acid, and the gradient elution procedure was used. The blood sample was treated with protein precipitant with acetonitrile–methanol (9:1, v/v). Multiple reaction monitoring mode was used for quantitative analysis in electrospray positive‐ion mode. It showed a good linear relationship in the range of 1–4000?ng/mL (r?>?0.998); the intra‐day and inter‐day precision was <12%, and the accuracy was 86–112%. The recovery was >68%, and the matrix effect was 86–90%. The half‐life of isoscoparin was relatively short in mice, and the bioavailability was 2.6%. The developed UPLC–MS/MS method was rapid, sensitive, and suitable for the pharmacokinetics of isoscoparin in mice.
查看更多>>摘要：Abstract Alzheimer's disease (AD) is regarded as a progressive neurodegenerative dementia, characterized by degeneration of distinct neuronal populations. A case–control study was carried out using high‐resolution mass spectrometry to explore AD‐associated urinary metabolic biomarkers from 30 AD patients and 30 cognitively normal (CN) individuals. In total, 49 metabolites were determined and validated as known compounds using LC/MS analysis. Using the two‐sample t‐test statistical analysis (P?<?0.05), 19 metabolites were shown to be significantly different from AD to CN. A diagnostic model of the receiver operating characteristic curve was constructed with a combination of nine?molecules out of 19 metabolites, it yielded a separation with an area under the curve value of 0.976 between the two groups. This study indicated that urinary metabolites showed a significant expression between AD and CN. AD‐related metabolites enable to satisfy the diagnostic power of disease discrimination. In addition, as a noninvasive approach, urine collection is done easily in clinical diagnosis of AD.
查看更多>>摘要：Abstract Cyclocarya paliurus (CP) extracts have been shown to lower sugar and lipid levels in blood, but the material basis is not clear. We analyzed CP aqueous extracts using high‐performance liquid chromatography “fingerprinting”, checked their pharmacological parameters using virtual screening, and undertook molecular docking and molecular dynamics simulations. Also, the inhibitory effects of CP components upon α‐glucosidase in vitro were evaluated. Fingerprinting and virtual screening showed that the aqueous extract of CP contained the active components protocatechuic acid, chlorogenic acid, caffeic acid and rutin, which were safe and had no side effects in vivo. Molecular docking and molecular dynamics simulations showed that chlorogenic acid and rutin might have a potent inhibitory effect on α‐glucosidase. An enzyme‐activity assay in vitro showed that the half‐maximal inhibitory values of chlorogenic acid and rutin were 398.9 and 351.8?μg/ml, respectively. Chlorogenic acid and rutin had an inhibitory effect on α‐glucosidase. Cyclocarya paliurus could be developed as a natural α‐glucosidase inhibitor.
Priyanka A. ShahVinay S. SharmaPravin G. VanolMallika Sanyal...
9页
查看更多>>摘要：Abstract A reliable and robust bioanalytical method was developed to quantify neratinib, a tyrosine kinase inhibitor in human plasma, using UPLC–MS/MS. The extraction of neratinib and its deuterated internal standard, neratinib‐d6, was successfully performed on hybrid solid‐phase extraction ultra‐cartridges to remove the interference of phospholipids and proteins. Chromatographic analysis was performed on a UPLC BEH C18 (50?×?2.1 mm, 1.7 μm) column using 0.1% formic acid and acetonitrile under gradient conditions. The total analysis time was 1.5?min. Neratinib was quantified using electrospray ionization source operated in the positive‐ion multiple reaction monitoring mode. The mass transitions of neratinib and neratinib‐d6 were m/z 557.3/112.1 and m/z 563.1/118.2, respectively. The linear concentration range for neratinib was 0.5–500?ng/mL, which adequately covers concentration levels expected in real subject samples. The assay was extensively validated for various validation parameters following standard guidelines for a bioanalytical assay. The intra‐ and inter‐batch precision was ≤4.6%, and neratinib was found to be stable under various stability conditions. The mean internal standard–normalized matrix factor and recovery were 0.997 and 95.4%, respectively. The validated method was successfully applied to a pharmacokinetic study in healthy subjects with different doses.
查看更多>>摘要：Abstract The analgesic effect of the resin of Boswellia carterii (BC) is well known; however, the constituents that contribute to the analgesic effect remain elusive. The current study integrates ultrasonic‐assisted extraction, quantitative determination, analgesic evaluation in rats, and gray relationship analysis for tracing analgesic constituents from the resin of BC. First, a robust and precise ultra‐performance liquid chromatography tandem mass spectrometry approach with multiple reaction monitoring mode was developed for the simultaneous quantification of seven major constituents in crude and vinegar‐processed resin of BC. Glycyrrhetinic acid was chosen as the internal standard. The approach showed good linearity. The intra‐ and inter‐day precisions of each constituent were within 3.0%. The recoveries of each constituent were in the range of 96.4–102.7%. The approach was then applied to determine the seven constituents in 10 batches of crude and vinegar‐processed resin of BC. Second, the analgesic effects of crude and vinegar‐processed resin of BC were assessed in mice. Third, chemometrics methods, gray relationship analysis, and partial least squares regression were employed for determining the relationship between the contents of seven constituents and their analgesic effects. 11‐Keto‐β‐boswellic acid, 3‐acetyl‐β‐boswellic acid, 3‐acetyl‐α‐boswellic acid, 3‐acetyl‐11‐keto‐β‐boswellic acid, and β‐sitosterol were identified as the key analgesic constituents of BC.
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