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Rotundic acid(RA),an ursane-type pentacyclic triterpene acid isolated from the dried barks of Ilex rotunda Thunb.(Aquifoliaceae),possesses diverse bioactivities.To further study its pharmacokinetics,a simple and sensitive liquid chromatography with triple quadrupole mass spectrometry(LC-QqQ-MS/MS)method was developed and validated to quantify RA concentration in rat plasma and tissue using etofesalamide as an internal standard(IS).Plasma and tissue samples were subjected to one-step protein precipitation.Chromatographic separation was achieved on a ZORBAX Eclipse XDB-C18 col-umn(4.6 mm×50 mm,5 μm)under gradient conditions with eluents of methanol:acetonitrile(1∶1,V/V)and 5mM ammonium formate:methanol(9∶1,V/V)at 0.5mL/min.Multiple reaction monitoring transitions were performed at m/z 487.30 → 437.30 for RA and m/z 256.10 → 227.10 for IS in the negative mode.The developed LC-QqQ-MS/MS method exhibited good linearity(2-500 ng/mL)and was fully validated in accordance with U.S.Food and Drug Administration bioanalytical guidelines.Dose proportionality and bioavailability in rats were determined by comparing pharmacokinetic data after single oral(10,20,and 40 mg/kg)and intravenous(10 mg/kg)administration of RA.Tissue distribution was studied following oral administration at 20 mg/kg.The results showed that the absolute bioavailability of RA after administration at different doses ranged from 16.1％to 19.4％.RA showed good dose proportionality over a dose range of 10-40 mg/kg.RA was rapidly absorbed in a dose-dependent manner and highly distributed in the liver.In conclusion,this study is the first to systematically elucidate the absorption and distribution characteristics of RA in rats,which can provide additional information for further development and evaluation of RA in drug metabolism and pharmacokinetic studies.
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AIM: To establish an LC-MS/MS method to determine the concentration of ambrisentan in human plasma and apply it to the study of human pharmacokinetics. METHODS: After extracting ambrisentan and internal standard from human plasma by liquid-liquid extraction, chromatographic separation was performed on a Waters Symmetry C
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Aim TodevelopandvalidateaLC-MS/MS assay to quantify halometasone in rabbit plasma and study pharmacokinetics of halometasone after dermal topical administration of Halometasone Cream.Meth-ods Theplasmasamplewassubmittedtoliquid-liquid extraction using methyl tertiary butyl ether,with dexa-methasone as the internal standard (IS ).Chromato-graphic separations were performed on a Diamonsil C18 column(100 mm ×4. 6 mm,5 μm)with a linear gra-dient of methanol and 2 mmol · L-1 ammonium ace-tate.Halometasone and dexamethasone(IS)were ion-ized with an ESI source operated in negative ion mode, and the detected ions were m/z 503. 1→413. 0 (halo-metasone),m/z 391. 0→361. 0 (dexamethasone ). The test article could be monitored in rabbit plasma when following single dermal topical administration of Halometasone Cream at 1 g/100 cm2 to rabbits by u-singavalidatedLC-MS/MSassay.Results Calibra-tion curve was linear over the concentration range of0. 02~20 μg·L-1 in rabbit plasma.For low,medi-um,high concentration of QC solutions,the intra-and inter-day precision was in the range of 3. 72% ~7. 87%, and the accuracy was within 99. 1% to 103%. The pharmacokinetic parameters in rabbits were as follows:Tmax,Cmax,AUC0-t,T1/2 was (7. 38 ± 1. 06)h,(1. 16 ±0. 527)μg·L-1,(18. 8 ±7. 23)h·μg·L-1 ,(13. 8 ±3. 70)h,respectively.Conclusions ThisLC-MS/MSanalysismethodhashighsensitivi-ty,and sample processing method is simple,which has been rigorously validated.The method could be suc-cessfully applied to the pharmacokinetic study of halo-metasone after skin administration of Halometasone Cream to rabbits.
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The previous investigation has proved that their existed pharmacokinetic difference between the different crystal forms of the polymorphic drugs after oral administration. However, no systemic investigations have been made on the change of this pharmacokinetic difference, resulted either from the physiological or from the pathological factors. In this paper, we used polymorphic nimodipine (Nim) as a model drug and investigated the effect of age difference (2- and 9-month old) on the pharmacokinetics after oral delivery in rats. As the results shown, for L-form of Nim (L-Nim), the AUCin 2-month-old rats was 343.68±47.15 ng·h/mL, which is 23.36% higher than that in 9-month-old rats. For H-form of Nim (H-Nim), the AUCin 2-month-old rats was 140.91±19.47 ng·h/mL, which is 54.64% higher than that in 9-month-old rats. The AUCratio between H-Nim and L-Nim was 2.44 in 2-month-old rats and 3.06 in 9-month-old rats. Since age difference could result in unparallelled change of the absorption and bioavailability of the polymorphic drugs, the results in this experiment are of value for further investigation of crystal form selection in clinical trials and rational clinical application of the polymorphic drugs.
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Deoxyglycychloxazol (TY501) is a glycyrrhetinic acid derivative which exhibits high anti-inflammatory activity and reduced pseudoaldosteronism compared to glycyrrhetinic acid. In this study, a sensitive and rapid liquid chromatography–tandem mass spectrometry (LC–MS/MS) method was established for the quantitation of TY501 in rat plasma. Plasma samples were treated by precipitating protein with methanol and supernatants were separated by a Symmetry C8 column with the mobile phase consisting of me-thanol and 10 mM ammonium formate (containing 0.1%of formic acid) (90:10, v/v). The selected reaction monitoring (SRM) transitions were performed at m/z 647.4-191.2 for TY501 and m/z 473.3-143.3 for astragaloside aglycone (IS) in the positive ion mode with atmospheric pressure chemical ionization (APCI) source. Calibration curve was linear over the concentration range of 5–5000 ng/mL. The lower limit of quantification was 5 ng/mL. The mean recovery was over 88%. The intra-and inter-day precisions were lower than 6.0% and 12.8%, respectively, and the accuracy was within 71.3%. TY501 was stable under usual storage conditions and handling procedure. The validated method has been successfully applied to a pharmacokinetic study after oral administration of TY501 to rats at a dosage of 10 mg/kg.
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A rapid, sensitive and simple liquid chromatography-tandem mass spectrometry (LC-MS/MS) method was developed and validated for the simultaneous determination of clevidipine butyrate and its primary metabolite clevidipine acid in dog blood. After one-step protein precipitation with methanol, the chromatographic separation was carried out on an Ecosil C18 column (150 mm x 4.6 mm, 5 µm) with a gradient mobile phase consisting of methanol and 5 mmol · L(-1) ammonium formate. A chromatographic total run time of 13.0 min was achieved. The quantitation analysis was performed using multiple reaction monitoring (MRM) at the specific ion transitions of m/z 454.1 [M-H]- --> m/z 234.1 for clevidipine butyrate, m/z 354.0 [M-H]- --> m/z 208.0 for clevidipine acid and m/z 256.1 [M-H]- --> m/z 227.1 for elofesalamide (internal standard, IS) in the negative ion mode with electrospray ionization (ESI) source. The linear calibration curves for clevidipine butyrate and clevidipine acid were obtained in the concentration ranges of 0.5-100 ng · mL and 1-200 ng · mL(-1), separately. The lower limit of quantification of clevidipine butyrate and clevidipine acid were 0.5 ng · mL(-1) and 1 ng · mL(-1). The intra and inter-assay precisions were all below 12.9%, the accuracies were all in standard ranges. Stability testing indicated that clevidipine butyrate and clevidipine acid in dog blood with the addition of denaturant methanol was stable under various processing and/or handling conditions. The validated method has been successfully applied to a pharmacokinetic study of clevidipine butyrate injection to 8 healthy Beagle dogs following intravenous infusion at a flow rate of 5 mg · h(-1) for 0.5 h.
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Aim To develop a simple,rapid and ac-curate analysis method for determination of chiral ibu-profen in Beagle dog plasma.Method The plasma sample was submitted to liquid - liquid extraction u-sing hexane /isopropanol (95 ∶5,V/V),with ketopro-fen as the internal standard (IS).The separation was accomplished in a Lux 5u Cellulose-3 (250 mm·4.6 mm,5 μm)column,and the mobile phase consisted of methanol and a mixture of 1 mmol·L -1 ammonium acetate-methanol-formic acid (90 ∶1 0 ∶0.2,V/V/V) with the volume ratio of 82 ∶1 8 at a flow rate of 0.8 mL· min -1 .The mass spectrometer consisted of an ESI interface operating at negative ionization mode and the detection was performed using multiple reaction monitoring at the transitions of m /z 205.2 /1 61 .2 for ibuprofen and m /z 253.1 /209.2 for ketoprofen (IS). Method validation included the evaluation of the matrix effect, extraction recovery, linearity, lower LOQ, within-run and between-run precision,stability and di-lution effect.Results The calibration curve was line-ar across the concentration range of 0.2 ~50 mg·L -1 for each ibuprofen enantiomer with a lower LOQ of 0.2 mg·L -1 .The within-run and between-run precision (RSD%)was in the range 1 .01 % ~1 3.1 % for each ibuprofen.The pharmacokinetic parameters for orally single dose of (S +)and racemic ibuprofen in Beagle dogs were as follows: Cmax , T1 /2 , AUC(0-t) were (82.98 ±1 4.83 )mg·L -1 ,(3.21 7 ±0.7298)h, (362.0 ±58.67)h·mg·L -1 for (S +)ibuprofen and 70.62 /74.48 mg·L -1 ,1 .520 /5.432 h ,1 77.8 /649.6 h·mg·L -1 for (R -)/(S +)ibuprofen,re-spectively.Conclusions A simple,rapid,accurate, high sensitivity and repeatability method has been suc-cessfully developed,which can analyze the concentra-tions of (R -)/(S +)ibuprofen in Beagle dog plasma simultaneously.The method could be applied for the investigation of pharmacokinetics of ibuprofen enanti-omers in Beagle dogs.
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Objective: To evaluate the pharmacokinetics of palonosetron hydrochloride in healthy volunteers. Methods: Thir-ty-one healthy volunteers were grouped into three palonosetron hydrochloride dosage regimens of 0.125, 0.25, and 0.5 mg. The plasma concentrations of palonosetron were determined by ultra high-performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS). DAS 2.1 software was applied to assess the plasma concentration-time data. Results:After intravenous injection of 0.125, 0.25, and 0.5 mg palonosetron to the subjects, the AUC0-168h values of palonosetron were (7.5±2.5), (15.2±4.0), and (34.8±9.7) μg· h·mL-1. The t1/2 values were (27.2±9.5), ( 27.2±6.5), and (31.4±5.6) h. Palonosetron exposure increased proportionally with the dose range of 0.125 mg to 0.5 mg. The correlation coefficient was 0.998. No grade 3 or grade 4 toxicity was observed during the study. Con-clusion:A rapid, sensitive, and selective UPLC-MS/MS method for palonosetron quantification in human plasma was developed and validated. All the participants indicated high tolerance throughout the study. Our data showed that palonosetron exhibits linear pharma-cokinetics over the the dose range of 0.125 mg to 0.5 mg.
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In this review, the author analyzed the challenges in modern research and development of Traditional Chinese Medicine (TCM) products. Chinese traditional and herb drugs have gained interest from the international medical, biomedical and pharmaceutical institutions as potential source of valuable medicinal agents. For the researches and development of TCMs, the first challenge is to evaluate the efficacy, pharmacological properties, action mechanism and active chemical constituents. The second one is to summarize the issues for developing safety research methodologies, to improve the quality and enhance the value of research in TCM and to provide appropriate evaluation methods to facilitate the regulation and registration of TCM products, and the third is to study drug metabolism and pharmacokinetics, and the fourth is to apply new "-omics" techniques and tools in new revolution in drug discovery-development and to impact on modern research of TCM products. This interest is needed to apply modern research on the development and exploration of the promising medical potential resources of Chinese traditional and herbal drugs, especially from medicinal plants.
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Gender-related differences in drug pharmacokinetics have frequently been considered as potentially important determinants for the clinical effectiveness of drug therapy. Major molecular factors involved in drug disposition include drug-metabolising enzymes and drug transporters. Oxidative drug metabolism by cytochrome P450 (CYP) enzymes is a major pathway for drug elimination. CYP3A4,the major human drug-metabolizing CYP enzymes,has repeatedly been suggested higher metabolic activity in women than that in men,which sex-dependent secretory patterns of growth hormone that may be responsible for.
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Objective: To observe effects of Ficus carica polysaccharide (FCPS) on tumor bearing mice. Methods: The model of S 180 bearing mice and EAC bearing mice were established, tumor cells were inoculated under the skin of right armpit or in abdominal cavity in mice after FCPS being administered orally for ten days, to calculate inhibitive rate of tumor and survial time of mice. Results: FCPS could significantly prevent the growth of tumor, there were no effects on survival time of mice.Conclusion: FCPS had a good antineoplastic effect. It is worth further study.
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AIM: To study the protetive effects of Danshenhonghua Injection (Radix Salviae Miltiorrhizae,Stigma Croci,etc) on acute cerebral ischemia in rats. METHODS : The model of acute incomplete cerebral ischemia was built by ligaturing bilateral carotid arteries. Cerebral index,cerebral water content ,capillary permeability of brain,and the change of cerebral morphology in rats were observed. RESULTS : The cerebral index,cerebral water content,capillary permeability of brain decreased remarkably with 7.2,14.4mg?kg -1 of Danshenhonghua Injection,and the injury of brain tissue was also abated by Danshenhonghua Injection significantly. CONCLUSION : Danshenhonghua Injection has the protetive effects on acute cerebral ischemia.