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 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 Pharmacokinetics, Tissue Distribution and Excretion of a Novel Diuretic (PU-48) in Rats

Pharmaceutics ◽  
2018 ◽  
Vol 10 (3) ◽  
pp. 124 ◽  
Author(s):  
Zhi-Yuan Zhang ◽  
Hua Zhang ◽  
Dan Liu ◽  
Ying-Yuan Lu ◽  
Xin Wang ◽  
...  
Keyword(s):  
Oral Administration ◽  
Tissue Distribution ◽  
High Performance ◽  
Peak Plasma ◽  
Plasma Concentrations ◽  
Area Under The Curve ◽  
Pharmacokinetic Profile ◽  
Rat Plasma ◽  
Drug Candidate ◽  
Liquid Chromatography Tandem Mass

Methyl 3-amino-6-methoxythieno [2,3-b] quinoline-2-carboxylate (PU-48) is a novel diuretic urea transporter inhibitor. The aim of this study is to investigate the profile of plasma pharmacokinetics, tissue distribution, and excretion by oral dosing of PU-48 in rats. Concentrations of PU-48 within biological samples are determined using a validated high performance liquid chromatography-tandem mass spectrometry (LC-MS/MS) method. After oral administration of PU-48 (3, 6, and 12 mg/kg, respectively) in self-nanomicroemulsifying drug delivery system (SNEDDS) formulation, the peak plasma concentrations (Cmax), and the area under the curve (AUC0–∞) were increased by the dose-dependent and linear manner, but the marked different of plasma half-life (t1/2) were not observed. This suggests that the pharmacokinetic profile of PU-48 prototype was first-order elimination kinetic characteristics within the oral three doses range in rat plasma. Moreover, the prototype of PU-48 was rapidly and extensively distributed into thirteen tissues, especially higher concentrations were detected in stomach, intestine, liver, kidney, and bladder. The total accumulative excretion of PU-48 in the urine, feces, and bile was less than 2%. This research is the first report on disposition via oral administration of PU-48 in rats, and it provides important information for further development of PU-48 as a diuretic drug candidate.

scholarly journals Characterization of hyperglycemia due to sub-chronic administration of red ginseng extract via comparative global proteomic analysis

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Ann-Yae Na ◽  
Jung Jae Jo ◽  
Oh Kwang Kwon ◽  
Piljoung Cho ◽  
Yan Gao ◽  
...  
Keyword(s):  
Proteomic Analysis ◽  
Herbal Remedy ◽  
Chronic Administration ◽  
Serum Glucose ◽  
Control Group ◽  
Red Ginseng ◽  
Korean Red Ginseng ◽  
Ginseng Extract ◽  
Glucose Levels ◽  
Term Administration

AbstractGinseng (Panax ginseng Meyer) is commonly used as an herbal remedy worldwide. Few studies have explored the possible physiological changes in the liver although patients often self-medicate with ginseng preparations, which may lead to exceeding the recommended dose for long-term administration. Here, we analyzed changes in the hepatic proteins of mouse livers using quantitative proteomics after sub-chronic administration of Korean red ginseng (KRG) extract (control group and 0.5, 1.0, and 2.0 g/kg KRG) using tandem mass tag (TMT) 6‐plex technology. The 1.0 and 2.0 g/kg KRG groups exhibited signs of liver injury, including increased levels of aspartate transaminase (AST) and alanine aminotransferase (ALT) in the serum. Furthermore, serum glucose levels were significantly higher following KRG administration compared with the control group. Based on the upregulated proteins found in the proteomic analysis, we found that increased cystathionine beta-synthase (CBS) and cystathionine gamma-lyase (CSE) levels promoted greater hydrogen sulfide (H2S) synthesis in the liver. This investigation provides novel evidence that sub-chronic administration of KRG can elevate H2S production by increasing protein expression of CBS and CSE in the liver.

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.

scholarly journals Comparative Study on Pharmacokinetics of Four Active Compounds in Rat Plasma after Oral Administration of Raw and Wine Processed Chuanxiong Rhizoma

Molecules ◽  
2019 ◽  
Vol 25 (1) ◽  
pp. 93 ◽  
Author(s):  
Yan Ning ◽  
Ke Pei ◽  
Gang Cao ◽  
Hao Cai ◽  
Xiao Liu ◽  
...  
Keyword(s):  
Oral Administration ◽  
Negative Ions ◽  
Rat Plasma ◽  
Phase System ◽  
Exact Mass ◽  
Active Compounds ◽  
Liquid Chromatography Tandem Mass ◽  
Ultrahigh Performance Liquid Chromatography ◽  
Switching Mode ◽  
T Values

In Chinese medicine, the effect of promoting blood circulation and removing stasis could be enhanced after Chuanxiong Rhizoma is processed by wine. However, the relevant mechanism remains unclear. In this manuscript, a rapid and sensitive quantification method employing ultrahigh performance liquid chromatography-tandem mass spectrometry (UHPLC-MS/MS) was established and validated to simultaneously determine butylidenephthalide, ligustilide, senkyunolide A and ferulic acid in rat plasma after oral administration of raw Chuanxiong Rhizoma (RCR) and wine-processed Chuanxiong Rhizoma (WCR) respectively. All analytes were extracted from plasma by proteins precipitation with methanol. Chromatographic separation was carried out on a Hypersil GOLD C18 column by using a gradient mobile phase system of acetonitrile and water with 0.01% formic acid, the flow rate was 0.3 mL/min. For exact mass detecting, quick switching mode was used, positive and negative ions could be detected in one injection. The pharmacokinetic profiles of four components in the two groups were evaluated and compared. The results showed that, compared to the RCR group, the Vd and AUC0→t values of four active compounds were increased and decreased respectively in WCR group, which revealed the effect of wine processing to Chuanxiong Rhizoma: the stronger the effect, the wider the distribution.

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