scholarly journals Detection of 13 Ginsenosides (Rb1, Rb2, Rc, Rd, Re, Rf, Rg1, Rg3, Rh2, F1, Compound K, 20(S)-Protopanaxadiol, and 20(S)-Protopanaxatriol) in Human Plasma and Application of the Analytical Method to Human Pharmacokinetic Studies Following Two Week-Repeated Administration of Red Ginseng Extract

Molecules ◽  
2019 ◽  
Vol 24 (14) ◽  
pp. 2618 ◽  
Author(s):  
Sojeong Jin ◽  
Ji-Hyeon Jeon ◽  
Sowon Lee ◽  
Woo Youl Kang ◽  
Sook Jin Seong ◽  
...  
Keyword(s):  
Human Plasma ◽  
Analytical Method ◽  
Plasma Concentrations ◽  
Repeated Administration ◽  
Pharmacokinetic Studies ◽  
Red Ginseng ◽  
Compound K ◽  
Ginseng Extract ◽  
Limit Of Quantitation ◽  
Liquid Chromatography Tandem Mass

We aimed to develop a sensitive method for detecting 13 ginsenosides using liquid chromatography–tandem mass spectrometry and to apply this method to pharmacokinetic studies in human following repeated oral administration of red ginseng extract. The chromatograms of Rb1, Rb2, Rc, Rd, Re, Rf, Rg1, Rg3, Rh2, F1, compound K (CK), protopanaxadiol (PPD), and protopanaxatriol (PPT) in human plasma were well separated. The calibration curve range for 13 ginsenosides was 0.5–200 ng/mL and the lower limit of quantitation was 0.5 ng/mL for all ginsenosides. The inter- and intra-day accuracy, precision, and stability were less than 15%. Among the 13 ginsenosides tested, nine ginsenosides (Rb1, Rb2, Rc, Rd, Rg3, CK, Rh2, PPD, and PPT) were detected in the human plasma samples. The plasma concentrations of Rb1, Rb2, Rc, Rd, and Rg3 were correlated with the content in red ginseng extract; however, CK, Rh2, PPD, and PPT were detected although they are not present in red ginseng extract, suggesting the formation of these ginsenosides through the human metabolism. In conclusion, our analytical method could be effectively used to evaluate pharmacokinetic properties of ginsenosides, which would be useful for establishing the pharmacokinetic–pharmacodymic relationship of ginsenosides as well as ginsenoside metabolism in humans.

scholarly journals Simultaneous Determination and Pharmacokinetic Characterization of Glycyrrhizin, Isoliquiritigenin, Liquiritigenin, and Liquiritin in Rat Plasma Following Oral Administration of Glycyrrhizae Radix Extract

Molecules ◽  
2019 ◽  
Vol 24 (9) ◽  
pp. 1816 ◽  
Author(s):  
You Jin Han ◽  
Bitna Kang ◽  
Eun-Ju Yang ◽  
Min-Koo Choi ◽  
Im-Sook Song
Keyword(s):  
Oral Administration ◽  
Analytical Method ◽  
Plasma Concentrations ◽  
Rat Plasma ◽  
Pharmacokinetic Studies ◽  
Elution Time ◽  
Glycyrrhizae Radix ◽  
Single Oral Administration ◽  
Limit Of Quantitation ◽  
Liquid Chromatography Tandem Mass

Glycyrrhizae Radix is widely used as herbal medicine and is effective against inflammation, various cancers, and digestive disorders. We aimed to develop a sensitive and simultaneous analytical method for detecting glycyrrhizin, isoliquiritigenin, liquiritigenin, and liquiritin, the four marker components of Glycyrrhizae Radix extract (GRE), in rat plasma using liquid chromatography-tandem mass spectrometry and to apply this analytical method to pharmacokinetic studies. Retention times for glycyrrhizin, isoliquiritigenin, liquiritigenin, and liquiritin were 7.8 min, 4.1 min, 3.1 min, and 2.0 min, respectively, suggesting that the four analytes were well separated without any interfering peaks around the peak elution time. The lower limit of quantitation was 2 ng/mL for glycyrrhizin and 0.2 ng/mL for isoliquiritigenin, liquiritigenin, and liquiritin; the inter- and intra-day accuracy, precision, and stability were less than 15%. Plasma concentrations of glycyrrhizin, isoliquiritigenin, liquiritigenin, and liquiritin were quantified for 24 h after a single oral administration of 1 g/kg GRE to four rats. Among the four components, plasma concentration of glycyrrhizin was the highest and exhibited a long half-life (23.1 ± 15.5 h). Interestingly, plasma concentrations of isoliquiritigenin and liquiritigenin were restored to the initial concentration at 4–10 h after the GRE administration, as evidenced by liquiritin biotransformation into isoliquiritigenin and liquiritigenin, catalyzed by fecal lysate and gut wall enzymes. In conclusion, our analytical method developed for detecting glycyrrhizin, isoliquiritigenin, liquiritigenin, and liquiritin could be successfully applied to investigate their pharmacokinetic properties in rats and would be useful for conducting further studies on the efficacy, toxicity, and biopharmaceutics of GREs and their marker components.

scholarly journals Effects of Red Ginseng Extract on the Pharmacokinetics and Elimination of Methotrexate via Mrp2 Regulation

Molecules ◽  
2018 ◽  
Vol 23 (11) ◽  
pp. 2948 ◽  
Author(s):  
Sowon Lee ◽  
Mihwa Kwon ◽  
Min-Koo Choi ◽  
Im-Sook Song
Keyword(s):  
Oral Administration ◽  
Plasma Concentrations ◽  
Repeated Administration ◽  
Rat Plasma ◽  
Control Group ◽  
Red Ginseng ◽  
Ginseng Extract ◽  
Protein Levels ◽  
Liquid Chromatography Tandem Mass ◽  
Dosing Regimens

We aimed to investigate the effects of red ginseng extract (RGE) on the expression of efflux transporters and to study the pharmacokinetics of representative substrate. For this, rats received single or repeated administration of RGE (1.5 g/kg/day) for 1 and 2 weeks via oral gavage. mRNA and protein levels of multidrug resistance-associated protein2 (Mrp2), bile salt export pump (Bsep), and P-glycoprotein (P-gp) in the rat liver were measured via real-time polymerase chain reaction and Western blot analysis. Ginsenosides concentrations from the rat plasma were also monitored using a liquid chromatography–tandem mass spectrometry (LC–MS/MS) system. Plasma concentrations of ginsenoside Rb1, Rb2, Rc, and Rd following repeated administration of RGE for 1 and 2 weeks were comparable but significantly higher than those after single administration of RGE. These dosing regimens did not induce significant biochemical abnormalities in the liver, kidneys, and lipid homeostasis. In the RGE repeated oral administration groups, the mRNA and protein levels of Mrp2 significantly decreased. Accordingly, we investigated the changes in the pharmacokinetics of methotrexate, a probe substrate for Mrp2, following intravenous administration of 3 mg/kg methotrexate to rats in the RGE 1-week repeated oral administration group, compared to that in the control group. Biliary excretion, but not urinary excretion, of methotrexate decreased in the RGE repeated administration group, compared to that in the control group. Consequently, the plasma concentrations of methotrexate slightly increased in the RGE repeated administration group. In conclusion, repeated administration of RGE for 1 week resulted in a decrease in Mrp2 expression without inducing significant liver or kidney damage. Pharmacokinetic herb–drug interaction between RGE and methotrexate might occur owing to the decrease in the mRNA and protein levels of Mrp2.

scholarly journals DEVELOPMENT AND VALIDATION OF BIOANALYTICAL HPLC METHOD FOR SIMULTANEOUS ESTIMATION OF CILNIDIPINE AND NEBIVOLOL IN HUMAN PLASMA

2017 ◽  
Vol 9 (10) ◽  
pp. 253
Author(s):  
Aruna G. ◽  
Bharathi K ◽  
Kvsrg Prasad
Keyword(s):  
Human Plasma ◽  
Analytical Method ◽  
Internal Standard ◽  
Hplc Method ◽  
Pharmacokinetic Parameters ◽  
Simultaneous Estimation ◽  
Time Data ◽  
Bioanalytical Method Validation ◽  
Limit Of Quantitation ◽  
The Mean

Objective: To develop and validate a modified isocratic reversed-phase high performance liquid chromatographic (RP-HPLC) method for determination of cilnidipine and nebivolol in human plasma to be used for pharmacokinetic studies.Methods: The drug was extracted from plasma samples by direct protein precipitation technique using acetonitrile. Amlodipine was used as internal standard (IS). Samples were analyzed on BDS C18 column (250 x 4.6 mm, 5 µm), applying ortho phosphoric acid (0.1%): Acetonitrile, at a ratio of 45:55 v/v in isocratic mode as a mobile phase at a flow rate of 1 ml/min to attain adequate resolution. Separations were performed at room temperature and monitored at a wavelength of 260 nm after injection of 50μl samples into the HPLC system. The analytical method was validated according to FDA bioanalytical method validation guidance. The method was applied for pharmacokinetic study of cilnidipine and nebivolol tablets-10 mg and 5 mg were administered as a single dose to 6 healthy male rabbits under fasting condition. Twelve blood samples were withdrawn from each rabbit over 24 h periods. From the plasma concentration-time data of each individual, the pharmacokinetic parameters; Cmax, Tmax, AUC0-t and AUC0-∞ were calculated.Results: A peak area was obtained for cilnidipine and nebivolol at 3.943 and 4.719 min retention time respectively. Linearity was established at a concentration range of 0.20-20 μg/ml (r2=0.999, n=8) for cilnidipine and 0.02-2 μg/ml (r2=0.999, n=8) for nebivolol. The lower limit of quantitation (LLOQ) was identifiable and reproducible at 0.2μg/ml for cilnidipine and 0.02 μg/ml for nebivolol. The coefficients of variation (%cv) of the intra-day and inter-day precision of cilnidipine at 600, 1000 and 1600ng/ml levels were found to be 6.90%, 6.19%, 5.22%; and 7.74%, 6.54%, 5.77%, respectively, which are lower than the accepted criteria limits (15-20 %). The mean recovery (%) cilnidipine at 600, 1000, and 1600ng/ml was found to be 101.03%, 99.27% and 104.87%, and for nebivolol 60, 100, and 160 ng/ml was found to be 106.13%, 107.03% and 98.06% respectively. Stability at different conditions and in autosampler was also established. The mean pharmacokinetic parameters; Cmax, Tmax, AUC0-t and AUC0-∞ were 6 ng/ml, 2 hr, 96.76 mg. hr/ml, 63.45 mg. hr/ml for cilnidipine and 5.8ng/ml, 2hr, 74.78 mg. hr/ml, 100.25 mg. hr/ml for nebivolol respectively.Conclusion: The present analytical method was found to be specific, sensitive, accurate and precise for quantification of cilnidipine and nebivolol in human plasma. It can be successively applied for pharmacokinetics, bioavailability and bioequivalence studies.

scholarly journals Enhanced Intestinal Permeability and Plasma Concentration of Metformin in Rats by the Repeated Administration of Red Ginseng Extract

Pharmaceutics ◽  
2019 ◽  
Vol 11 (4) ◽  
pp. 189 ◽  
Author(s):  
Sojeong Jin ◽  
Sowon Lee ◽  
Ji-Hyeon Jeon ◽  
Hyuna Kim ◽  
Min-Koo Choi ◽  
...  
Keyword(s):  
Plasma Concentration ◽  
Intestinal Permeability ◽  
Lucifer Yellow ◽  
Repeated Administration ◽  
Tissue Type ◽  
Pharmacokinetic Analysis ◽  
Mrna Levels ◽  
Red Ginseng ◽  
Korean Red Ginseng ◽  
Ginseng Extract

We aimed to assess the potential herb–drug interactions between Korean red ginseng extract (RGE) and metformin in rats in terms of the modulation of metformin transporters, such as organic cation transporter (Oct), multiple toxin and extrusion protein (Mate), and plasma membrane monoamine transporter (Pmat). Single treatment of RGE did not inhibit the in vitro transport activity of OCT1/2 up to 500 µg/mL and inhibited MATE1/2-K with high IC50 value (more than 147.8 µg/mL), suggesting that concomitant used of RGE did not directly inhibit OCT- and MATE-mediated metformin uptake. However, 1-week repeated administration of RGE (1.5 g/kg/day) (1WRA) to rats showed different alterations in mRNA levels of Oct1 depending on the tissue type. RGE increased intestinal Oct1 but decreased hepatic Oct1. However, neither renal Oct1/Oct2 nor Mate1/Pmat expression in duodenum, jejunum, ileum, liver, and kidney were changed in 1WRA rats. RGE repeated dose also increased the intestinal permeability of metformin; however, the permeability of 3-O-methyl-d-glucose and Lucifer yellow was not changed in 1WRA rats, suggesting that the increased permeability of metformin by multiple doses of RGE is substrate-specific. On pharmacokinetic analysis, plasma metformin concentrations following intravenous injection were not changed in 1WRA, consistent with no significant change in renal Oct1, Oct2, and mate1. Repeated doses of RGE for 1 week significantly increased the plasma concentration of metformin, with increased half-life and urinary excretion of metformin following oral administration of metformin (50 mg/kg), which could be attributed to the increased absorption of metformin. In conclusion, repeated administration of RGE showed in vivo pharmacokinetic herb–drug interaction with metformin, with regard to its plasma exposure and increased absorption in rats. These results were consistent with increased intestinal Oct1 and its functional consequence, therefore, the combined therapeutic efficacy needs further evaluation before the combination and repeated administration of RGE and metformin, an Oct1 substrate drug.

Simultaneous determination of novel ketolide antibiotic nafithromycin and its major metabolite in human plasma using liquid chromatography tandem mass spectrometry

Bioanalysis ◽  
2019 ◽  
Vol 11 (19) ◽  
pp. 1767-1776
Author(s):  
Kiran R Patil ◽  
Ravindra D Yeole ◽  
Marcel de Zwart ◽  
Peter Pruim
Keyword(s):  
Phase I ◽  
Human Plasma ◽  
Internal Standard ◽  
Pharmacokinetic Studies ◽  
Simultaneous Quantification ◽  
Chromatography Tandem Mass Spectrometry ◽  
Liquid Chromatography Tandem Mass ◽  
Us Fda ◽  
Standard Protein

Aim: A sensitive method to quantify nafithromycin and its N-desmethyl metabolite in human plasma was necessary for Phase I pharmacokinetic studies. Methodology: A precise and accurate LC–MS/MS bioanalytical method has been developed and validated for the simultaneous quantification of nafithromycin (NFT, WCK 4873) and N-desmethyl metabolite (M1, WCK 4978) in human plasma. Clarithromycin was used as an internal standard. Protein precipitation technique was used as sample preparation approach. The calibration curve was linear (r ≥ 0.99) over the concentration range of 10–5000 ng/ml for NFT and M1. Method was validated as per US FDA guideline. Conclusion: The proposed method was successfully applied for determination of plasma levels of the NFT and M1 during Phase I clinical studies.

scholarly journals Reliable and Easy-To-Use Liquid Chromatography-Tandem Mass Spectrometry Assay for Quantification of Olorofim (F901318), a Novel Antifungal Drug, in Human Plasma and Serum

2018 ◽  
Vol 62 (11) ◽  
Author(s):  
Carsten Müller ◽  
Cornelia Fietz ◽  
Philipp Koehler ◽  
Graham Sibley ◽  
Achu Che Awah Nforbugwe ◽  
...  
Keyword(s):  
Mass Spectrometry ◽  
Liquid Chromatography ◽  
Tandem Mass Spectrometry ◽  
Human Plasma ◽  
Antifungal Drug ◽  
Selected Reaction Monitoring ◽  
Tandem Mass ◽  
Chromatography Tandem Mass Spectrometry ◽  
Limit Of Quantitation ◽  
Liquid Chromatography Tandem Mass

ABSTRACT A fast and easy-to-use liquid chromatography-tandem mass spectrometry (LC-MS/MS) method for the determination and quantification of a novel antifungal drug, olorofim (F901318), a member of the novel class of orotomides, in human plasma and serum was developed and validated. Sample preparation was based on protein precipitation with acetonitrile and subsequent centrifugation. An isotope-labeled analogue of F901318 was employed as an internal standard. Chromatographic separation was achieved using a 50-mm by 2.1-mm, 1.9-μm, polar Hypersil Gold C18 column and isocratic mobile phase consisting of 0.1% formic acid–acetonitrile (60%-40%, vol/vol) at a flow rate of 330 μl/min. The analyte was detected using a triple-stage quadrupole mass spectrometer operated in selected reaction monitoring (SRM) mode with positive heated electrospray ionization (HESI+) within a single runtime of 2.00 min. The present LC-MS/MS method was validated according to the international guidelines of the International Conference on Harmonisation (ICH) and the U.S. Food and Drug Administration (FDA). Linearity of F901318 concentration ranges was verified by the Mandel test. The calibration curve was tested linear across the range and fitted using least-squares regression with a weighting factor of the reciprocal concentration. The limit of detection was 0.0011 mg/liter, and the lower limit of quantitation was 0.0033 mg/liter. Intraday and interday precisions ranged from 1.17% to 3.23% for F901318, and intraday and interday accuracies (percent bias) ranged from 0.75% to 5.01%. In conclusion, a method was established for the rapid quantitation of F901318 concentrations in serum and plasma samples in patient trials, and it optimizes therapeutic drug monitoring in applying an easy-to-use single method.

scholarly journals Ultra-performance liquid chromatography–tandem mass spectrometric determination of ramipril in human plasma

2020 ◽  
Vol 19 (4) ◽  
pp. 851-857
Author(s):  
Sherif A. Abdel-Gawad
Keyword(s):  
Liquid Chromatography ◽  
Human Plasma ◽  
Internal Standard ◽  
The United States ◽  
Ultra Performance Liquid Chromatography ◽  
Mass Spectrometric ◽  
Pharmacokinetic Studies ◽  
Tandem Mass ◽  
Liquid Chromatography Tandem Mass ◽  
Tandem Mass Spectrometric

Purpose: To develop a sensitive and accurate ultra-performance liquid chromatography–tandem mass spectrometric (UPLC-MS) method for quantification of ramipril in human plasma.Methods: Ramipril was extracted from biological fluid using equal volumes of n-hexane and propanol (1:1, v/v), and then chromatographed in a suitable C18 column with methanol: 0.1 % HCOOH (4: 1, v/v) as mobile phase. Atorvastatin was used as an internal standard for the  chromatographic separation and quantification. The method was validated according to the United States Food and Drug Administration guidelines for standard indices.Results: Ramipril was determined in the concentration range 0.05 and 1000 ng/mL the validation procedure exhibited a correlation coefficient of 0.9979 + 0.002 (p = 0.05). The studied drug was quantified with lower ceiling of 0.05 ng/mL, and showed an accuracy of 105.00 %.Conclusion: A sensitive UPLC-MS analytical method has been successfully developed for the quantification of ramipril in human plasma. This method can be applied efficiently for the quantification of ramipril in bioavailability and pharmacokinetic studies. Keywords: Liquid chromatography–tandem mass, Ramipril, Stability, Biological fluids, Plasma

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