ABSTRACT
Hong-Hua-Xiao-Yao tablet (HHXYT) is attracting attention increasingly because of its use in treatment of mammary gland hyperplasia (MGH) and menopausal syndrome. However, its pharmacokinetics remains unclear. This study developed a sensitive and rapid method for simultaneous determination of 10 compounds of HHXYT in rat plasma by liquid chromatography-tandem mass spectrometry and to compare the pharmacokinetics of these compounds in MGH rats and sham operated rats. The linearity, accuracy, precision, stability and matrix effect were within acceptable ranges. This established method was successfully applied to a pharmacokinetics study of 10 compounds in sham operated and MGH rats. According to the results, the bioavailability of glycyrrhetinic acid was highest in MGH rats and sham operated rats. The mean residence times of glycyrrhetinic acid and glycyrrhetinic acid 3-O-glucuronide were higher than those of the other compounds while the mean residence time and half-life of liquiritin, isoliquiritin and paeoniflorin were lower. Some pharmacokinetic parameters of ormononetin, liquiritigenin, isoliquiritigenin, liquiritin, isoliquiritin, paeoniflorin, protocatechuic acid and senkyunolide I were significantly different between MGH rats and sham operated rats. This study elucidated the dynamic changes of multiple components in rats after oral administration of HHXYT systematically and comprehensively, which provided guidance for clinical application.
Subject(s)
Drugs, Chinese Herbal , Rats, Sprague-Dawley , Tandem Mass Spectrometry , Animals , Rats , Drugs, Chinese Herbal/pharmacokinetics , Drugs, Chinese Herbal/administration & dosage , Drugs, Chinese Herbal/chemistry , Tandem Mass Spectrometry/methods , Reproducibility of Results , Female , Linear Models , Chromatography, Liquid/methods , Tablets/pharmacokinetics , Chalcones/pharmacokinetics , Chalcones/chemistry , Chalcones/blood , Biological Availability , Limit of Detection , Glycyrrhetinic Acid/pharmacokinetics , Glycyrrhetinic Acid/blood , Glycyrrhetinic Acid/chemistryABSTRACT
A rapid, sensitive, and accurate ultra flow liquid chromatography tandem mass spectrometry (UFLC-MS/MS ) method was developed and validated for simultaneous quantitation of glycyrrhetic acid and puerarin in plasma derived from healthy and alcoholic liver injury rats. Plasma samples from healthy and model rats were deproteinated with methanol using liquiritin as an internal standard. Chromatography separation was performed by a Waters BEH (ethylene-bridged hybrid) C18 column (2.1 × 50 mm; 1.7 µm) using a gradient elution from acetonitrile and water (containing 0.1% formic acid) and at a flow rate of 0.4 mL/min. Quantitation was performed on a Triple Quad 4500 tandem mass spectrometer coupled with an electrospray ionization source in negative multiple reaction monitoring mode. Specificity, carryover, dilution integrity, recovery, linearity, precision and accuracy, matrix effect, and stability were within acceptable limits. The newly established method was successfully applied to a pharmacokinetics study to investigate glycyrrhetic acid and puerarin in healthy and alcoholic liver injury rats.
Subject(s)
Chemical and Drug Induced Liver Injury/metabolism , Chromatography, High Pressure Liquid/methods , Glycyrrhetinic Acid/blood , Isoflavones/blood , Tandem Mass Spectrometry/methods , Animals , Ethanol/adverse effects , Glycyrrhetinic Acid/chemistry , Glycyrrhetinic Acid/pharmacokinetics , Isoflavones/chemistry , Isoflavones/pharmacokinetics , Limit of Detection , Linear Models , Liver/metabolism , Male , Rats , Rats, Sprague-Dawley , Reproducibility of ResultsABSTRACT
The aim of this study was to confirm pharmacokinetic screening of multiple components in healthy Korean subjects after oral administration of Samso-eum and perform quantitation of active components in the human plasma. Thirteen potential bioactive components [puerarin (PRR), daidzin, nodakenin, ginsenoside Rb1, 18ß-glycyrrhetinic acid (18ß-GTA), 6-shogaol, naringin, glycyrrhizin, hesperidin, platycodin D, naringenin, hesperetin, and 6-gingerol] were screened based on literature. The results showed that three analytes (daidzin, naringenin, and hesperetin) were detected in trace amounts. In addition, PRR and 18ß-GTA were detected in human plasma after the oral administration of Samso-eum. In this study, a liquid chromatography-electrospray ionization-tandem mass spectrometry method was validated for the simultaneous determination of PRR and 18ß-GTA in human plasma. This was the first study to evaluate pharmacokinetics of PRR and 18ß-GTA after the usual oral dose of Samso-eum (30 g containing 102.48 mg PRR, 48.18 mg glycyrrhizin) in human subjects.
Subject(s)
Chromatography, Liquid/methods , Drugs, Chinese Herbal , Glycyrrhetinic Acid/analogs & derivatives , Isoflavones/blood , Tandem Mass Spectrometry/methods , Administration, Oral , Adult , Drugs, Chinese Herbal/administration & dosage , Drugs, Chinese Herbal/pharmacokinetics , Glycyrrhetinic Acid/blood , Glycyrrhetinic Acid/chemistry , Glycyrrhetinic Acid/pharmacokinetics , Humans , Isoflavones/chemistry , Isoflavones/pharmacokinetics , Limit of Detection , Linear Models , Male , Reproducibility of Results , Young AdultABSTRACT
Background: High-dose methotrexate (HD-MTX) therapy is widely implemented for leukemia, osteosarcoma, and lymphoma. Although various measures have been taken to avoid toxicity from high serum MTX concentrations, there are many cases of delayed elimination of MTX. Objective: We suspected that delayed elimination of serum MTX was caused by unknown interactions between MTX and concomitant drugs. Methods: Concerning concomitant drugs in the case of delayed elimination of MTX, we performed screening tests in 35 patients who had undergone HD-MTX therapy. We then investigated the risk factors for delayed MTX elimination in 94 patients with leukemia, lymphoma, or osteosarcoma retrospectively. Results: The percentages of concomitant use of Stronger Neo-Minophagen C (SNMC), a glycyrrhizin preparation, and vincristine were higher in the delayed group. The percentage of delayed MTX elimination in patients receiving HD-MTX therapy was 41%. Multiple logistic regression analysis revealed that the concomitant use of SNMC solely was a significant risk factor for delayed MTX (odds ratio = 12.20; 95% CI = 1.06-139.84). Conclusion and Relevance: Concomitant use of SNMC was shown to be related to delayed elimination of serum MTX, and our results suggested a previously unknown drug-drug interaction between MTX and SNMC.
Subject(s)
Drug Monitoring/methods , Methotrexate/administration & dosage , Methotrexate/blood , Cysteine/administration & dosage , Cysteine/blood , Cysteine/therapeutic use , Drug Combinations , Drug Interactions , Female , Glycine/administration & dosage , Glycine/blood , Glycine/therapeutic use , Glycyrrhetinic Acid/administration & dosage , Glycyrrhetinic Acid/analogs & derivatives , Glycyrrhetinic Acid/blood , Glycyrrhetinic Acid/therapeutic use , Humans , Leukemia/blood , Leukemia/drug therapy , Logistic Models , Lymphoma/blood , Lymphoma/drug therapy , Male , Metabolic Clearance Rate , Methotrexate/therapeutic use , Osteosarcoma/blood , Osteosarcoma/drug therapy , Retrospective Studies , Risk Factors , Vincristine/administration & dosage , Vincristine/blood , Vincristine/therapeutic useABSTRACT
Zhiqiao Gancao (ZQGC) decoction is widely used in China due to its therapeutic effect on lumbar disc herniation (LDH). In this study, we compared the clinical therapeutic effects among oral ZQGC decoction treatment, bed rest, and oral anti-inflammatory drug celecoxib treatment using visual analog scale, Oswestry Disability Index, and MacNab scores. The results showed that ZQGC decoction can significantly improve the symptoms of patients with LDH. A selective, sensitive, and rapid ultra-performance liquid chromatography-tandem mass spectrometry method was developed and validated for the determination of eight bioactive components in rat plasma. The plasma samples were extracted by simple protein precipitation with methanol. The protonated analytes were quantitated simultaneously in positive and negative ion modes by multiple reaction monitoring with a mass spectrometer. The calibration curve of eight components in plasma showed good linearity (r > .996) and the extraction recovery was 81.19% ± 2.15% - 100.39 ± 3.36 (relative standard deviation: 1.21%-10.70%). The accuracy of all the lower limit of quantitation values was quantified within 80%-120%, and the precision was less than 15%. This validated method was successfully applied to the pharmacokinetics study in rat plasma after ZQGC decoction oral treatment. Our research can provide experimental basis for the rational clinical application of ZQGC decoction in the treatment of LDH.
Subject(s)
Analgesics/therapeutic use , Drugs, Chinese Herbal/pharmacokinetics , Drugs, Chinese Herbal/therapeutic use , Administration, Oral , Analgesics/administration & dosage , Analgesics/blood , Analgesics/pharmacokinetics , Animals , Curcumin/analysis , Curcumin/pharmacokinetics , Drugs, Chinese Herbal/administration & dosage , Drugs, Chinese Herbal/analysis , Flavones/blood , Flavones/pharmacokinetics , Glycyrrhetinic Acid/blood , Glycyrrhetinic Acid/pharmacokinetics , Humans , Intervertebral Disc Degeneration/drug therapy , Intervertebral Disc Degeneration/physiopathology , Intervertebral Disc Displacement/drug therapy , Intervertebral Disc Displacement/physiopathology , Linear Models , Male , Rats , Rats, Sprague-Dawley , Reproducibility of Results , Sensitivity and SpecificityABSTRACT
A simple and sensitive liquid chromatography with tandem mass spectrometry method was developed for simultaneous quantification of paeoniflorin, albiflorin, oxypaeoniflorin, liquiritin, liquiritigenin, glycyrrhetinic acid, and glycyrrhizin in rat plasma after oral administration of Shaoyao-Gancao decoction, which is traditionally used in the treatment of polycystic ovary syndrome. The plasma samples were pretreated with methanol as precipitant. The method exhibited good linearity (correlation coefficient (R2 ) > 0.99) with lower quantification limits of 0.595-4.69 ng/mL for all analytes. Intra- and interbatch precision, accuracy, recovery, and stability of the method were all within accepted criteria. The results showed that the pharmacokinetic behaviors of the seven compounds were altered in the pathological status of polycystic ovary syndrome. Furthermore, a total of 36 metabolites were structurally identified based on their accurate masses and fragment ions. The major metabolic pathway involves phase I metabolic reactions (such as hydroxylation), phase II metabolic reactions (such as sulfation and glucuronidation conjugation) as well as the combined multiple-step metabolism. This study is the first report on the pharmacokinetic and metabolic information of Shaoyao-Gancao decoction in both normal and model rats, which would provide scientific evidences for the bioactive chemical basis of herbal medicines and also promote the clinical application of Shaoyao-Gancao decoction for treating polycystic ovary syndrome.
Subject(s)
Drugs, Chinese Herbal/therapeutic use , Polycystic Ovary Syndrome/drug therapy , Administration, Oral , Animals , Bridged-Ring Compounds/blood , Bridged-Ring Compounds/metabolism , Bridged-Ring Compounds/pharmacokinetics , Chromatography, High Pressure Liquid , Drugs, Chinese Herbal/administration & dosage , Drugs, Chinese Herbal/analysis , Drugs, Chinese Herbal/metabolism , Drugs, Chinese Herbal/pharmacokinetics , Female , Flavanones/blood , Flavanones/metabolism , Flavanones/pharmacokinetics , Glucosides/blood , Glucosides/metabolism , Glucosides/pharmacokinetics , Glycyrrhetinic Acid/blood , Glycyrrhetinic Acid/metabolism , Glycyrrhetinic Acid/pharmacokinetics , Glycyrrhizic Acid/blood , Glycyrrhizic Acid/metabolism , Glycyrrhizic Acid/pharmacokinetics , Monoterpenes/blood , Monoterpenes/metabolism , Monoterpenes/pharmacokinetics , Rats , Rats, Sprague-Dawley , Tandem Mass SpectrometryABSTRACT
Xuanmai Ganjie Granules (XMGJ), a widely used Chinese herbal formula in the clinic, is used for treatment of sore throats and coughs. Despite the chemical constituents having been clarifying by our previous studies, both of the metabolism and pharmacokinetic studies of XMGJ are unclear. This study aimed to explore the disposition process of XMGJ in vivo. A sensitive and selective ultra-high performance liquid chromatography with quadrupole time-of-flight mass spectrometry (UPLC-Q-TOF-MS) method was developed to analyze the absorbed components and metabolites in rat plasma and urine after oral administration of XMGJ. A total of 42 absorbed components, including 16 prototype compounds and 26 metabolites, were identified or tentatively characterized in rat plasma and urine after oral administration of XMGJ. Moreover, the pharmacokinetic studies of five compounds of XMGJ were investigated using ultra-high liquid chromatography with tandem mass spectrometry method. The results indicated that liquiritin, harpagoside, glycyrrhetic acid, liquiritigenin, formononetin and their metabolites might be the major components involved in the pharmacokinetic and metabolism process of XMGJ. This research showed a comprehensive investigation of XMGJ in vivo, which could provide a meaningful basis for further material basis and pharmacological as well as toxicological research.
Subject(s)
Chromatography, High Pressure Liquid/methods , Drugs, Chinese Herbal , Tandem Mass Spectrometry/methods , Administration, Oral , Animals , Drugs, Chinese Herbal/analysis , Drugs, Chinese Herbal/metabolism , Drugs, Chinese Herbal/pharmacokinetics , Flavonoids/blood , Flavonoids/metabolism , Flavonoids/pharmacokinetics , Flavonoids/urine , Glycosides/blood , Glycosides/metabolism , Glycosides/pharmacokinetics , Glycosides/urine , Glycyrrhetinic Acid/blood , Glycyrrhetinic Acid/metabolism , Glycyrrhetinic Acid/pharmacokinetics , Glycyrrhetinic Acid/urine , Limit of Detection , Linear Models , Metabolome , Pyrans/blood , Pyrans/metabolism , Pyrans/pharmacokinetics , Pyrans/urine , Rats , Reproducibility of ResultsABSTRACT
To study the pharmacokinetics of Erhuang decoction extracts, a high performance liquid chromatography-tandem mass spectrometry (HPLC-MS/MS) method was established for the determination of effective substances in rat plasma. The extracts prepared by water extraction (WE) method were given to rats by oral administration. After collected from the orbital venous plexus, plasma was treated by protein precipitation method. Then, the concentration of index components, including baicalin, liquiritin, berberine, palmatine and glycyrrhetinic acid, were determined by HPLC-MS/MS. Gradient elution mode was used to the chromatographic separation with an Inertsil ODS-SP column (100 mm×2.1mm, 5µm), with acetonitrile and 0.1% formic acid containing 10mmolL-1 ammonium acetate as the mobile phase. MS analysis was conducted by multiple reactions monitoring (MRM) with Electrospray Ionization (ESI). The extraction recoveries of the five active ingredients from plasma were greater than 86.04%, and the intra- and inter-day precisions were less than 16.57%. Results indicated that active ingredients in plasma of rats with oral administration of extracts showed certain difference in the pharmacokinetic parameters, which proved that the active ingredients were effectively absorbed. The established HPLC-MS/MS analytical method was sensitive and accurate, suitable for the pharmacokinetic study of active ingredients in Erhuang decoction.
Subject(s)
Chromatography, High Pressure Liquid/methods , Drugs, Chinese Herbal/pharmacokinetics , Tandem Mass Spectrometry/methods , Administration, Oral , Animals , Berberine/blood , Berberine Alkaloids/blood , Coptis chinensis , Drugs, Chinese Herbal/administration & dosage , Flavanones/blood , Glucosides/blood , Glycyrrhetinic Acid/blood , Glycyrrhiza/chemistry , Glycyrrhiza/metabolism , Rats , Rats, Sprague-Dawley , Reproducibility of Results , Scutellaria baicalensis/chemistryABSTRACT
A highly sensitive liquid chromatography tandem mass spectrometry (LC-MS/MS) method for simultaneous determination of glycyrrhizin (GL) and its active metabolite, glycyrrhetinic acid (GA), from human plasma was validated and applied to a human pharmacokinetic study. The analytes were extracted from human plasma using an Oasis MAX cartridge and chromatographic separation was performed on an Inertsil ODS-3 column. The detection was performed using an API 4000 mass spectrometer operating in the positive electrospray ionization mode. Selected ion monitoring transitions of m/z 823 â 453 for GL and m/z 471 â 149 for GA were obtained. The response was a linear function of concentration over the ranges of 0.5-200 ng/mL for GL and 2-800 ng/mL for GA (both R2 > 0.998). Using this method, the pharmacokinetics of GL after single oral administration of a clinical dose (75 mg) to six healthy male Japanese volunteers were evaluated. GL was detected in the plasma of all subjects and the average peak concentration was 24.8 ± 12.0 ng/mL. In contrast, peak concentration of GA was 200.3 ± 60.3 ng/mL, i.e. ~8-fold higher than that of GL. This is the first report clarifying pharmacokinetic profiles of GL and GA simultaneously at a therapeutic oral dose of a GL preparation.
Subject(s)
Chromatography, Liquid/methods , Glycyrrhetinic Acid/blood , Glycyrrhetinic Acid/pharmacokinetics , Glycyrrhizic Acid/blood , Glycyrrhizic Acid/pharmacokinetics , Administration, Oral , Adult , Glycyrrhetinic Acid/chemistry , Glycyrrhizic Acid/administration & dosage , Glycyrrhizic Acid/chemistry , Humans , Linear Models , Male , Reproducibility of Results , Sensitivity and Specificity , Tandem Mass Spectrometry/methodsABSTRACT
Rapid, sensitive, selective and accurate UPLC-MS/MS method was developed and fully validated for simultaneous determination of cinnamaldehyde, cinnamic acid, 2-methoxy cinnamic acid, glycyrrhizic acid, glycyrrhetinic acid, liquiritigenin and isoliquiritin in rat plasma after oral administration of Guizhi-gancao decoction. Plasma samples were processed with a simple protein precipitation technique using acetonitrile, followed by chromatographic separation using a Thermo Hypersil GOLD C18 column. A 11.0min linear gradient elution was used at a flow rate of 0.2mL/min with a mobile phase of 0.1% acetic acid containing 0.2mM ammonium acetate in water and acetonitrile. The analytes and internal standard, schisandrin, were detected using both positive and negative ion electrospray ionization in multiple reaction monitoring mode. The developed method was validated for intra-day and inter-day accuracy and precision whose values fell in the acceptable limits. Matrix effect was found to be minimal. Recovery efficiency of all the analytes was found to be >60%. Stability results showed that the analytes were stable at all the conditions. This validated method was successfully used to study the pharmacokinetics of multiple compounds in rat plasma after oral administration of Guizhi-gancao decoction.
Subject(s)
Chromatography, High Pressure Liquid/methods , Drugs, Chinese Herbal/administration & dosage , Drugs, Chinese Herbal/pharmacokinetics , Plasma/chemistry , Tandem Mass Spectrometry/methods , Administration, Oral , Animals , Chalcone/analogs & derivatives , Chalcone/blood , Chalcone/chemistry , Cinnamates/blood , Cinnamates/chemistry , Drugs, Chinese Herbal/chemistry , Flavanones/blood , Flavanones/chemistry , Glucosides/blood , Glucosides/chemistry , Glycyrrhetinic Acid/blood , Glycyrrhetinic Acid/chemistry , Glycyrrhizic Acid/blood , Glycyrrhizic Acid/chemistry , Male , Rats , Reproducibility of Results , Sensitivity and SpecificityABSTRACT
A sensitive, specific, accurate HPLC-MS/MS method was developed and validated for the simultaneous quantification of catechin, epicatechin, liquiritin, isoliquiritin, liquiritigenin, isoliquiritigenin, piperine and glycyrrhetinic acid from Longhu Rendan pills in rat plasma. Chromatographic separation was performed with a Hypersil Gold C18 column using a gradient of methanol and 0.01% acetic acid containing 0.2 mm ammonium acetate as mobile phase. The analytes were quantified on a triple quadrupole mass spectrometer, operating in selected reaction monitoring mode and switching the electrospray ion source polarity between positive and negative modes in a single run. The calibration curves of catechin, epicatechin, liquiritin, isoliquiritin, liquiritigenin, isoliquiritigenin, piperine and glycyrrhetinic acid were linear over the concentration ranges of 5-2000, 5-2000, 0.5-200, 0.5-200, 0.25-100, 0.25-100, 0.025-10 and 0.50-200 ng mL(-1) , respectively. The intra- and inter-assay precisions and accuracies were <11.6 and 91.9-108.2%, respectively, for all analytes. Matrix effects for all analytes were between 88.2 and 114.2%. Stability testing showed that all analytes were stable in plasma at 24 °C for 3 h, at 4 °C for 24 h, after three freeze-thaw cycles, and at -80 °C for 15 days. The method was successfully applied to an in vivo study evaluating the pharmacokinetics of multiple nonvolatile compounds following intragastric administration of Longhu Rendan pills to rats. Copyright © 2016 John Wiley & Sons, Ltd.
Subject(s)
Chromatography, High Pressure Liquid/methods , Drugs, Chinese Herbal/chemistry , Flavonoids/blood , Glycyrrhetinic Acid/blood , Tandem Mass Spectrometry/methods , Terpenes/blood , Animals , Calibration , Drugs, Chinese Herbal/pharmacokinetics , Flavonoids/pharmacokinetics , Glycyrrhetinic Acid/pharmacokinetics , Limit of Detection , Male , Rats , Rats, Sprague-Dawley , Reference Standards , Terpenes/pharmacokineticsABSTRACT
The present study was designed to investigate the effects of Laminaria japonica (Laminaria) on pharmacokinetics of glycyrrhetinic acid (GA) following oral administration of Liquorice extract in rats. Following oral administrations of single-dose and multi-dose Liquorice extract and Liquorice-Laminaria extract, respectively, plasma samples were obtained at various times and the concentrations of GA, liquiritigenin, and isoliquiritigenin were measured by LC-MS. The effects of Laminaria extract on pharmacokinetics of GA were also investigated, following single-dose and multidose of glycyrrhizic acid (GL). The effects of Laminaria extract on intestinal absorption of GA and GL were studied using the in situ single-pass intestinal perfusion model. The metabolism of GL to GA in the contents of small and large intestines was also studied. The results showed Liquorice-Laminaria extract markedly increased the plasma concentration of GA, accompanied by a shorter Tmax. Similar alteration was observed following multidose administration. However, pharmacokinetics of neither liquiritigenin nor isoliquiritigenin was affected by Laminaria. Similarly, Laminaria markedly increased concentration and decreased Tmax of GA following oral GL were observed. The data from the intestinal perfusion model showed that Laminaria markedly increased GL absorption in duodenum and jejunum, but did not affect the intestinal absorption of GA. It was found that Laminaria enhanced the metabolism of GL to GA in large intestine. In conclusion, Laminaria increased plasma exposures of GA following oral administration of liquorice or GL, which partly resulted from increased intestinal absorption of GL and metabolism of GL to GA in large intestine.
Subject(s)
Drug Interactions , Glycyrrhetinic Acid/blood , Glycyrrhiza/chemistry , Glycyrrhizic Acid/pharmacokinetics , Intestinal Absorption , Laminaria , Plant Extracts/pharmacology , Administration, Oral , Animals , Glycyrrhizic Acid/blood , Intestinal Mucosa/metabolism , Male , Plant Extracts/blood , Plant Extracts/pharmacokinetics , Rats, Sprague-DawleyABSTRACT
CONTEXT: Yokukansan (YKS) is a traditional Japanese herbal medicine called kampo medicine in Japan. Its extract comprises seven crude drugs: Atractylodis lanceae rhizoma, Poria, Cnidii rhizoma, Uncariae uncis cum ramulus, Angelicae radix, Bupleuri radix, and Glycyrrhizae radix. YKS is used to treat neurosis, insomnia, as well as behavioral and psychological symptoms of dementia. OBJECTIVE: To confirm the exposure and pharmacokinetics of the active components of YKS in healthy volunteers. DESIGN, SETTING, AND PARTICIPANTS: A randomized, open-label, 3-arm, 3-period, crossover trial was conducted on 21 healthy Japanese volunteers at the Kochi Medical University between May 2012 and November 2012. INTERVENTIONS: Single oral administration of YKS (2.5 g, 5.0 g, or 7.5 g/day) during each period. MAIN OUTCOME MEASURE: Plasma concentrations of three active compounds in YKS, namely 18ß-glycyrrhetinic acid (GA), geissoschizine methyl ether (GM), and hirsuteine (HTE). RESULTS: The mean maximum plasma concentrations (Cmax) of GM and HTE increased dose-dependently (ranges: 0.650-1.98 ng/mL and 0.138-0.450 ng/mL, respectively). The times to maximum plasma concentration after drug administration (tmax) were 0.500 h for GM and 0.975-1.00 h for HTE. The apparent elimination half-lives (t1/2) were 1.72-1.95 h for GM and 2.47-3.03 h for HTE. These data indicate the rapid absorption and elimination of GM and HTE. On the other hand, the Cmax, tmax, and t1/2 of GA were 57.7-108 ng/mL, 8.00-8.01 h, and 9.39-12.3 h, respectively. CONCLUSION: We demonstrated that pharmacologically active components of YKS are detected in humans. Further, we determined the pharmacokinetics of GM, HTE, and GA. This information will be useful to elucidate the pharmacological effects of YKS. TRIAL REGISTRATION: Japan Pharmaceutical Information Center JAPIC CTI-121811.
Subject(s)
Drugs, Chinese Herbal/pharmacokinetics , Medicine, Kampo , Plants, Medicinal/chemistry , Administration, Oral , Adult , Alkaloids/blood , Area Under Curve , Cross-Over Studies , Dose-Response Relationship, Drug , Drugs, Chinese Herbal/administration & dosage , Drugs, Chinese Herbal/chemistry , Female , Glycyrrhetinic Acid/analogs & derivatives , Glycyrrhetinic Acid/blood , Healthy Volunteers , Humans , Indole Alkaloids/blood , Japan , Male , Metabolic Clearance Rate , Molecular Structure , Young AdultABSTRACT
Kushen-Gancao Decoction (KGD) is a classic traditional Chinese herb combination in treating viral hepatitis and chronic liver diseases. This study aims to investigate the pharmacokinetic (PK) study of matrine (MT), oxymatrine (OMT), glycyrrhizic acid (GL) and glycyrrhetinic acid (GA) following oral administration of KGD in rats. A rapid, sensitive and reliable HPLC-MS/MS method was successfully developed for the simultaneous determination of MT, OMT, GL and GA in rat plasma. A Inertsil C18 analytical column was used with a gradient mobile phase system of methanol-ammonium acetate (5mM) with a flow rate of 0.5 mL/min. The analysis was performed on a positive and negative ionization electrospray mass spectrometer via multi reaction monitoring (MRM). Linear calibration curves were obtained for the following concentration range: 10-5000 ng/mL for MT, OMT and GL, 50-15,000 ng/mL for GA in rat plasma (R(2)>0.99). The lower limit of quantification (LLOQ) was 5 ng/mL (MT, OMT and GL) and 20 ng/mL (GA). The intra- and inter-day accuracies ranged from -7.91 to 9.10% and precisions (RSD) were within 15%. The analytes were found to be stable under short-term temperature conditions, post-preparative temperature conditions, and after three freeze-thaw cycles conditions. The validated method was successfully applied to a pharmacokinetic study in rats after oral administration of KGD.
Subject(s)
Alkaloids/pharmacokinetics , Chromatography, High Pressure Liquid/methods , Drugs, Chinese Herbal/pharmacokinetics , Glycyrrhizic Acid/pharmacokinetics , Quinolizines/pharmacokinetics , Tandem Mass Spectrometry/methods , Administration, Oral , Alkaloids/blood , Alkaloids/chemistry , Animals , Drugs, Chinese Herbal/administration & dosage , Drugs, Chinese Herbal/analysis , Glycyrrhetinic Acid/blood , Glycyrrhetinic Acid/chemistry , Glycyrrhetinic Acid/pharmacokinetics , Glycyrrhizic Acid/blood , Glycyrrhizic Acid/chemistry , Linear Models , Quinolizines/blood , Quinolizines/chemistry , Rats , Rats, Sprague-Dawley , Reproducibility of Results , Sensitivity and Specificity , MatrinesABSTRACT
One of the most common adverse effects of traditional Japanese kampo and traditional Chinese medicine is pseudoaldosteronism caused by licorice. In this review, the authors describe the mechanisms of licorice-induced pseudoaldosteronism by the pharmacokinetics of chemical constituents and its metabolites containing licorice. Glycyrrhizin (GL), the main constituent of licorice, is absorbed as glycyrrhetinic acid (GA), which is a metabolite of GL produced by enterobacteria before its release into the circulation. Circulating GA is metabolized in the liver to become 3-monoglucuronyl-glycyrrhetinic acid (3MGA), which is excreted into the bile via multidrug resistance protein 2 (Mrp2). If Mrp2 function is damaged for some reason, 3MGA is secreted from the liver into the circulation, and excreted into the urine via organic anion transporters expressed at the basolateral side of tubular epithelial cells. Circulating GA cannot be excreted into the urine since GA binds highly to serum albumin and thus does not pass through glomerular filtration and is not a substrate of transporters expressed on tubular epithelial cells. Licorice-induced pseudoaldosteronism develops due to the inhibition of type 2 11ß-hydrosteroid dehydrogenase (11ß-HSD2) which results in the accumulation of cortisol in tubular epithelial cells that activate mineral corticoid receptors to stimulate the excretion of potassium that results in hypokalemia. GA, unlike 3MGA, cannot pass through tubular epithelial cells and cannot inhibit the enzyme in the cells. Therefore, 3MGA may be a genuine causative agent for licorice-induced pseudoaldosteronism. When licorice is used, 3MGA in plasma or urine could function as a marker compound to prevent the adverse effects.
Subject(s)
Glycyrrhetinic Acid/analogs & derivatives , Glycyrrhiza/adverse effects , Glycyrrhiza/metabolism , Liddle Syndrome/chemically induced , 11-beta-Hydroxysteroid Dehydrogenase Type 2/antagonists & inhibitors , 11-beta-Hydroxysteroid Dehydrogenase Type 2/genetics , ATP Binding Cassette Transporter, Subfamily B/metabolism , Animals , Bile/metabolism , Biomarkers/blood , Biomarkers/urine , Glycyrrhetinic Acid/blood , Glycyrrhetinic Acid/urine , Humans , Kidney/drug effects , Kidney/enzymology , Kidney/metabolism , Liddle Syndrome/blood , Liddle Syndrome/urine , Medicine, Chinese Traditional , Medicine, Kampo , ATP-Binding Cassette Sub-Family B Member 4ABSTRACT
The current study aims to investigate the pharmacokinetic properties of Huangqin Tang on different oral doses. An LC-MS method for simultaneous determination of flavonoids and terpenoids in rat plasma was developed and validated. Plasma samples were treated with hydrochloric acid (containing 1% ascorbic acid), precipitated with acetonitrile, separated on a Zorbax SB-C18 column, detected by single quadruple mass spectrometry with an electrospray ionization interface, and quantified using selected ion monitoring mode. All pharmacokinetic parameters were processed by non-compartmental analysis using WinNonlin software. The results of specificity, linearity, intra-day and inter-day precisions, accuracy, and stability for LC-MS assay were suitable for the quantification of paeoniflorin, baicalin, wogonoside, baicalein, wogonin, oroxylin A, glycyrrhizic acid and glycyrrhetinic acid in rat plasma. The concentration-time profiles of baicalin, wogonoside, baicalein, wogonin, oroxylin A and glycyrrhizic acid showed double-peak phenomenon after Huangqin Tang was orally administered at 40 g x kg(-1) dose; all eight constituents in rat plasma showed good dose-exposure relationship within the dosage of 10-40 g x kg(-1); although plasma concentrations were different, the flavonoids with the same backbone showed the similar fate in the body with the corresponding dosage. In conclusion, the LC-MS assay was successfully applied for the pharmacokinetic study of multi-constituents of Huangqin Tang with different doses. Additionally, these constituents demonstrated good pharmacokinetic properties in the body.
Subject(s)
Drugs, Chinese Herbal/chemistry , Flavanones/blood , Pentacyclic Triterpenes/blood , Administration, Oral , Animals , Chromatography, Liquid , Dose-Response Relationship, Drug , Drugs, Chinese Herbal/administration & dosage , Flavanones/pharmacokinetics , Flavonoids/blood , Flavonoids/pharmacokinetics , Glucosides/blood , Glucosides/pharmacokinetics , Glycyrrhetinic Acid/blood , Glycyrrhetinic Acid/pharmacokinetics , Glycyrrhizic Acid/blood , Glycyrrhizic Acid/pharmacokinetics , Male , Monoterpenes/blood , Monoterpenes/pharmacokinetics , Pentacyclic Triterpenes/pharmacokinetics , Rats , Rats, Wistar , Spectrometry, Mass, Electrospray IonizationABSTRACT
OBJECTIVES: The plasma pharmacokinetic profile in CD-1 mice of a novel 18ß-glycyrrhetinic acid (GA) derivative, which displays in vitro anti-cancer activity, was assessed. METHODS: This study involved an original one-step synthesis of N-(2-{3-[3,5-bis(trifluoromethyl)phenyl]ureido}ethyl)-glycyrrhetinamide, (2) a compound that displays marked anti-proteasome and anti-kinase activity. The bioselectivity profile of 2 on human normal NHDF fibroblasts vs human U373 glioblastoma cells was assessed. Maximal tolerated dose (MTD) profiling of 2 was carried out in CD1 mice, and its serum pharmacokinetics were profiled using an acute intravenous administration of 40 mg/kg body weight. KEY FINDINGS: Compound 2 displayed IC(50) in vitro growth inhibitory concentrations of 29 and 8 µm on NHDF fibroblasts and U373 glioblastoma cells, respectively, thus a bioselectivity index of â¼4. The intravenous pharmacokinetic parameters revealed that 2 was rapidly distributed (t(1/2dist) of â¼3 min) but slowly eliminated (t(1/2elim) = â¼77 min). CONCLUSIONS: This study describes an original and reliable nanoemulsion of a GA derivative with both anti-proteasome and anti-kinase properties and that should be further tested in vivo using various human xenograft or murine syngeneic tumour models with both single and chronic intravenous administration.
Subject(s)
Antineoplastic Agents/pharmacology , Glycyrrhetinic Acid/analogs & derivatives , Animals , Antineoplastic Agents/blood , Antineoplastic Agents/chemistry , Antineoplastic Agents/pharmacokinetics , Cell Line, Tumor , Chemistry, Pharmaceutical/methods , Dose-Response Relationship, Drug , Emulsions/chemistry , Emulsions/pharmacokinetics , Emulsions/pharmacology , Female , Fibroblasts/drug effects , Fibroblasts/metabolism , Glioblastoma/drug therapy , Glioblastoma/metabolism , Glycyrrhetinic Acid/blood , Glycyrrhetinic Acid/chemistry , Glycyrrhetinic Acid/pharmacokinetics , Glycyrrhetinic Acid/pharmacology , Humans , Mice , Particle Size , Proteasome Endopeptidase Complex/drug effects , Proteasome Endopeptidase Complex/metabolismABSTRACT
Licorice (glycyrrhiza root) has been used as a herbal medicine worldwide with its main active constituent being glycyrrhizin (GL). Licorice sometimes causes adverse effects such as inducing pseudoaldosteronism by inhibiting type 2 11ß-hydroxysteroid dehydrogenase (11ß-HSD2) caused by glycyrrhetinic acid (GA), a major metabolite of GL. In this study we compared the inhibitory effects of GA, GL, and 3-monoglucuronyl-glycyrrhetinic acid (3MGA), another metabolite of GL, on 11ß-HSD2 activity by using microsomes and rat kidney tissue slices. GA, 3MGA, and GL inhibited 11ß-HSD2 in rat kidney microsomes, with IC(50) values of 0.32, 0.26, and 2.2 µM, respectively. However, the inhibitory activity of these compounds was reduced markedly, in the slices, in a medium containing 5% bovine serum albumin. Assays using human embryonic kidney 293 cells with transient transformation in transporter genes showed that 3MGA is a substrate of human organic anion transporter (OAT) 1, human OAT3, and human organic anion-transporting peptide 4C1, whereas GA is not. When GA (100 mg/kg/day) was administered orally for 16 days to Eisai hyperbilirubinemic rats, plasma concentrations and urinary excretion of 3MGA were significantly higher, whereas the activity of 11ß-HSD2 in kidney microsomes was significantly lower compared with Sprague Dawley rats. These results suggest that 3MGA is actively transported into tubules through OATs, resulting in the inhibition of 11ß-HSD2. Because the plasma level of 3MGA depends on the function of hepatic transporters, monitoring 3MGA levels in plasma or urine may be useful for preventing pseudoaldosteronism when licorice or GL is prescribed to patients.
Subject(s)
11-beta-Hydroxysteroid Dehydrogenase Type 2/antagonists & inhibitors , 11-beta-Hydroxysteroid Dehydrogenase Type 2/metabolism , Epithelial Cells/metabolism , Glycyrrhetinic Acid/analogs & derivatives , Glycyrrhiza/toxicity , Liddle Syndrome/metabolism , Organic Anion Transporters/metabolism , Animals , Cell Line, Transformed , Epithelial Cells/enzymology , Glycyrrhetinic Acid/blood , Glycyrrhetinic Acid/metabolism , Glycyrrhetinic Acid/pharmacology , Glycyrrhetinic Acid/urine , Glycyrrhizic Acid/metabolism , Glycyrrhizic Acid/pharmacology , HEK293 Cells , Humans , Kidney/drug effects , Kidney/enzymology , Kidney/metabolism , Liddle Syndrome/chemically induced , Liddle Syndrome/enzymology , Liver/drug effects , Liver/enzymology , Liver/metabolism , Male , Microsomes/drug effects , Microsomes/enzymology , Microsomes/metabolism , Plants, Medicinal/toxicity , Rats , Rats, Sprague-Dawley , Rats, WistarABSTRACT
Consumption of large amounts of liquorice can cause hypertension and hypokalaemia. Liquorice contains glycyrrhetinic acid, which inhibits the enzyme 11 beta-hydroxysteroid dehydrogenase type 2, and ultimately leads to an apparent mineralocorticoid excess syndrome. This case report describes a 50 year-old woman presenting with hypertension and hypokalaemia-induced limb paresis due to chronic liquorice ingestion. The patient was treated with potassium supplementation and spironolactone. Her blood pressure and electrolyte status normalised within a month after cessation of liquorice intake.
Subject(s)
Candy/adverse effects , Glycyrrhiza/adverse effects , Hypertension/chemically induced , Hypokalemia/chemically induced , Female , Glycyrrhetinic Acid/blood , Humans , Hypertension/diagnosis , Hypokalemia/diagnosis , Middle AgedABSTRACT
An HPLC method for the determination of 18alpha-glycyrrhetinic acid and 18beta-glycyrrhetinic acid in rat plasma was established, which was used subsequently to determine the pharmacokinetic profiles of both epimers of glycyrrhetinic acid in rats. alpha-glycyrrhetinic acid, beta-glycyrrhetinic acid, and a mixture of alpha-glycyrrhetinic and beta-glycyrrhetinic acids were administered to rats via gastric infusion. Blood samples were collected at different time intervals and extracted by liquid-liquid extraction. Separation was achieved by using a Kromasil C18 column (150 mm x 4.6 mm, 5 microm) with the mobile phase composed of acetonitrile--4 mmol x L(-1) ammonium acetate solution (46 : 54, v/v) at a flow rate of 1.0 mL x min(-1), and the detection wavelength was set at 250 nm. The pharmacokinetic parameters were calculated using the software DAS 2.0. In a combined administration, the main pharmacokinetic parameters of beta-glycyrrhetinic acid are significantly different from that of alpha-glycyrrhetinic acid (P < 0.05), while no significant difference was obtained when administrated individually. Compared to the single administration, significant differences (P < 0.05) on the values of AUC(0-t) and AUC(0-infinity) of beta-glycyrrhetinic acid were observed when this chemical was administrated together with alpha-glycyrrhetinic acid. In contrast, the pharmacokinetic parameters of alpha-glycyrrhetinic acid were not affected even under the co-administration. Here, a sensitive, specific, rapid and reproducible HPLC method was developed for the pharmacokinetic studies of alpha-glycyrrhetinic acid and beta-glycyrrhetinic acid in rat plasma.