|Year : 2015 | Volume
| Issue : 44 | Page : 750-755
Pharmacokinetics, intestinal absorption and microbial metabolism of single platycodin D in comparison to Platycodi radix extract
Jinjun Shan1, Jiashuang Zou2, Tong Xie3, An Kang2, Wei Zhou3, Haishan Deng3, Yancao Mao2, Liuqing Di1, Shouchuan Wang3
1 Jiangsu Key Laboratory of Pediatric Respiratory Disease, Institute of Pediatrics; Jiangsu Engineering Research Center for Efficient Delivery System of TCM, College of Pharmacy, Nanjing University of Chinese Medicine, Nanjing 210023, China
2 Jiangsu Engineering Research Center for Efficient Delivery System of TCM, College of Pharmacy, Nanjing University of Chinese Medicine, Nanjing 210023, China
3 Jiangsu Key Laboratory of Pediatric Respiratory Disease, Institute of Pediatrics, Nanjing 210023, China
|Date of Submission||17-Nov-2014|
|Date of Acceptance||23-Dec-2014|
|Date of Web Publication||16-Sep-2015|
College of pharmacy, Nanjing University of Chinese Medicine, Nanjing 210023
Source of Support: This research is supported financially by the National
Natural Science Foundation of China (81001499), Conflict of Interest: None
| Abstract|| |
Background: Platycodi radix, the dried root of Platycodon grandiflorum A. DC, has been widely used as food and herb medicine for treating cough, cold and other respiratory ailments, and platycodin D (PD) is one of the most important compounds in Platycodi Radix. Objective: The purpose of this study was to compare the pharmacokinetic characteristics, intestinal absorption and microbial metabolism of PD in monomer with that in Platycodi radix extract (PRE). Materials and Methods: In the pharmacokinetic study, the concentrations of PD in rat plasma were determined by ultra-performance liquid chromatography-tandem mass spectrometry and the main pharmacokinetic parameters were calculated by data analysis software (DAS). Besides, in vitro Caco-2 cells and fecal lysate were performed to investigate the intestinal absorption and metabolism, respectively. Results: The results from pharmacokinetics showed that the area under the curve, the peak concentration the time to reach peak concentration and mean residence time of PD in PRE were enhanced significantly compared with that in single PD. Caco-2 cells transport study indicated that the absorption of PD both in monomer and in PRE were poor owning that the permeability of PD were <1/10 6 cm/s. The hydrolysis degree of PD in PRE was significantly lower than that in monomer PD in fecal lysate, which might be illustrated by the other ingredients in PRE influenced the hydrolysis of PD via gut microbiota. Conclusion: These findings indicated that the difference of microbial metabolism, not apparent absorption in intestine for PD between in monomer and in PRE contributed to their pharmacokinetic difference.
Keywords: Intestinal absorption, microbial metabolism, pharmacokinetics, Platycodi radix, platycodin D
|How to cite this article:|
Shan J, Zou J, Xie T, Kang A, Zhou W, Deng H, Mao Y, Di L, Wang S. Pharmacokinetics, intestinal absorption and microbial metabolism of single platycodin D in comparison to Platycodi radix extract. Phcog Mag 2015;11:750-5
|How to cite this URL:|
Shan J, Zou J, Xie T, Kang A, Zhou W, Deng H, Mao Y, Di L, Wang S. Pharmacokinetics, intestinal absorption and microbial metabolism of single platycodin D in comparison to Platycodi radix extract. Phcog Mag [serial online] 2015 [cited 2022 Aug 8];11:750-5. Available from: http://www.phcog.com/text.asp?2015/11/44/750/165576
Jinjun Shan, Jiashuang Zou
These authors contributed equally to this work
| Introduction|| |
Platycodi radix, the dried root of Platycodon grandiflorum A. DC, has been widely used as food and herb medicine for treatment of cough, cold, sore throat, tonsillitis, bronchitis, bronchial asthma, and other respiratory ailments. , Till now, more than 40 triterpenoid saponins, the major active components of P. radix, have been reported. ,, In these saponins, platycodin D (PD) shown in [Figure 1] have a high content in this crude drug, which applied as a chemical marker for the quality control of P. radix in the Chinese pharmacopeia (2010 edition).  The compound displays many beneficial properties,  such as anti-inflammatory, , hyperlipidemic, , anti-allergic properties,  as well as protective effects on oxidative hepatotoxicity,  stimulating apoptosis in cancer cells and exerting anticancer activities. ,,
It was reported that the oral absolute bio-availability of PD in monomer was significantly lower than that in Platycodi radix extract (PRE). ,, Thus, the pharmacokinetic profiles of single PD could not represent that in PRE, which might be demonstrated by the absorption or metabolism difference result from other components.
In this study, a comparative pharmacokinetic study was performed to investigate the differences of pharmacokinetic behaviors in rats after oral administration of PRE and single PD. Besides, Caco-2 cells and fecal lysate models were performed to investigate the transmembrane behavior and intestinal microbial metabolism of PD both in monomer and in PRE, respectively.
| Materials and methods|| |
The herb of P. radix was purchased from Nanjing Yifeng Pharmacy (Nanjing, China). Reference substances of PD and hesperidins (internal standard [IS]) were purchased from Sichuan Weikeqi Biological Technology Co., Ltd.(Chengdu, China). Both of the purities were above 98% by high-performance liquid chromatography (HPLC) analysis. Heated inactivity fetal bovine serum (FBS), trypsin-ethylenediaminetetraacetic acid (EDTA), Dulbecco's Modified Eagle's Medium (DMEM), nonessential amino acid solution, L-glutamine, penicillin-streptomycin, were purchased from Gibco Laboratory (Invitrogen Co, Grand Island, NY, USA). HPLC-grade acetonitrile was supplied by Merck (Darmstadt, Germany), and formic acid with a purity of 99% was of HPLC grade (ROE, USA). Deionized water (18 MΩ) was prepared by a Milli-Q system (Millipore, Milford, MA, USA). Other reagents and chemicals were of analytical grade.
Preparation of Platycodi radix extract
The herb of P. radix (50 g) was immersed in 500 mL deionized water for 0.5 h and then decocted to boil for 2 h. The extracted solution was filtered through two layers of gauze. Ethanol was added to the filtrate to precipitate the polysaccharide and protein. This sample was kept for 24 h at 4°C and then filtered through the filter paper and the filtrate was evaporated to obtain PRE, a final concentration of 1.0 g/mL (equivalent to dry weight of raw materials). The content of PD in PRE was quantitatively determined at 1.9 mg/mL by ultra-performance liquid chromatography-tandem mass spectrometry (UHPLC-MS/MS).
Animals and oral pharmacokinetic study
Male Sprague-Dawley rats (weighing 250 ± 20 g) were obtained from the Lab Animal Center of Nanjing University of Chinese Medicine and housed with free access to food and water. The experimental protocol was approved by the University Ethics Committee for the use of experimental animals and all animal studies were carried out according to the guide for care and use of laboratory animals. The animals were acclimatized to the facilities for 3 days, and then fasted for 12 h before each experiment.
Platycodi radix was used orally in clinics, and the typical dosage is 30-60 g/person (60 kg of body weight).  If the dosage in a rat was reasonably calculated by converting the human dosage with the conversion rate at 1:6.3 (human to rat), thus, the oral dosage in a rat PK study of PRE may be designed to be 6 g/kg. Meanwhile, the oral dosages of PRE in the previous studies and quantification sensitivity of instruments were all taken into consideration in our present study. Eventually, the oral dosage of PRE and PD was set at 10 g/kg and 20 mg/kg (corresponding equivalent PD), respectively.
The rats were randomized into two groups, six in each group: Rodents in group A were administered an oral dose of 20 mg/kg PD; rodents in group B were administered an oral dose of PRE (10 g/kg, corresponding equivalent PD). About 300 μL blood samples were collected into heparinized tubes via the postorbital venous plexus veins before drug administration and at 0.083, 0.167, 0.333, 0.667, 1, 2, 3, 4, 6, 8, 12 and 24 h after drug administration. Then the blood samples were immediately centrifuged at 5,000 rpm for 10 min and aliquots (100 μL) of plasma were spiked with 10 μL IS solution (92 ng/mL) by vortexing for 30 s, then 300 μL of methanol was added and the mixture was vortexed for 5 min. The well vortexed solutions were then centrifuged at 17,000 rpm for 10 min and separate the precipitated protein, 5 μL of the supernatant were injected into the UHPLC-MS/MS system for analysis.
To obtain the pharmacokinetic parameters of PD, the concentration time data were processed by noncompartmental methods using data analysis software (DAS, Version 3.0, Chinese Pharmacological Society, China). The parameter the time to reach peak concentration and Cmax (the peak concentration) of PD were obtained directly from the time point corresponding to peak concentration and peak concentration in rat plasma, respectively. Pharmacokinetic parameters including half-life, area under the curve (AUC), mean residence time (MRT) were determined by DAS software.
Caco-2 cell line was obtained from American Type Culture Collection, (Rockbille, MD, USA). Cells were grown routinely on 75 cm 2 plastic culture flasks (Becton Dickinson, Franklin Lakes, NJ, USA) in DMEM containing 25 mM D-glucose, 25 mM HEPES, 44 mM NaHCO 3 , supplemented with 10% (v/v) FBS, 1% (v/v) nonessential amino acid solution, 1% (v/v) L-glutanmine, 1% (v/v) penicillin-streptomycin at 37°C in an atmosphere of 5% CO 2 and 90% relative humidity. The medium was replaced every 2-3 days after incubation. Cells were passaged, 1:5, approximately every 5 days (at 70-80% confluence) using 0.25% trypsin and 0.02% EDTA. For the transport experiments, cells were seeded at a density of 5 × 10 4 cells/cm 2 onto permeable polycarbonate insert (0.6 cm 2 , 0.45 μm pore size, Millipore, USA) in 24-well tissue culture plates (NUNC, Roskilde, Denmark). Media in the culture plates was changed every 2 days for the 1 st week following seeding then replaced every day. Caco-2 monolayers were used for the experiments between days 21 and 24 postseeding. Cell passages between 32 and 40 were used in the experiment. The qualities of the monolayers grown on the permeable membrane were assessed by the transepithelial electrical resistance (TEER) of the monolayers at 37°C using a Millicell-ERS apparatus (Millipore, Bedford, MA, USA). Only monolayers displaying TEER values above 300 Ωcm 2 were used in the experiments, which indicated that the cell monolayers were not leaky.
Transcellular transporter of platycodin D across Caco-2 cell monolayer
The transport study across Caco-2 monolayer was investigated by a modified version of a previously published method . Briefly, 0.4 mL of PD solution (0.45 μg/mL) or PRE solution (corresponding equivalent PD) in hanks's balanced salt solution (HBSS) was loaded on apical side of the cell monolayer and 0.6 mL of blank HBSS onto the basolateral side. Aliquots of 0.1 mL and 0.15 mL of samples were taken sequentially at time points 0, 30, 60, 90, 120 min from doner and receiver side of the cell monolayer respectively. Drug solution and HBSS media were added to apical or basolateral side immediately to compensate for sampling volume lost. The pH of HBSS in both doner and receiver side was 7.4. A volume of 10 μL of an IS (92 ng/mL hesperidins in acetonitrile) was added to 100 μL samples right after sampling. Caco-2 samples were blown dried by nitrogen and reconstituted with 20 μL methanol for UHPLC-MS/MS.
The apparent unidirectional permeability, from apical to basolateral side (P app ), was calculated according to the following equation
where the d Q/d t (μg/min) is the drug permeation rate, A is the cross sectional area (0.6 cm 2 ), and C 0 (μg/mL) is the initial PD concentration in the donor compartment at t = 0 min.
Fecal lysate preparation
Fecal lysate was prepared by the method described previously with some modifications.  Briefly, Flesh feces of ten rats were collected, and about 1 g were immediately mixed with 9 mL ice-cold 0.1 mM phosphate buffer solution (PBS), (pH 7.4) and vortexed for 5 s followed by centrifugation at 1,000 rpm and 4°C for 15 min. The pellet was resuspended in 10 mL ice cold PBS, then sonicated in ice water bath for 45 min, and finally centrifuged at 15,000 rpm and 4°C for 30 min. The supernatant was aliqoted and stored at −70°C Protein concentrations were detected by the bicinchoninic acid protein assay kit with bovine serum albumin as the standard.
Hydrolysis of platycodin D in fecal lysate
Thawed fecal lysate (100 μL) was transferred to disposable glass vials, then 10 μL of PD solution (1.1 μg/mL) or PRE solution (0.5 mg/mL, corresponding equivalent PD) and 90 μL PBS solution were added to the samples. The mixture was incubated at 37°C and 120 rpm in an vapour-bathing constant temperature vibrator (Asheville, NC) for 48 h. Samples (100 μL) were collected at 0, 0.5, 1, 2, 4, 8, 12, 24, 36 and 48 h, then 10 μL of 92 ng/mL hesperidins (IS) in 100% methanol was immediately added to the collected sample to stop the reaction. The samples were vortexed for 3 min and centrifuged at 17,000 rpm for 10 min. The supernatant was injected into the UHPLC/MS-MS to for analysis of PD. Every given time experiments were performed independently in triplicate.
Quantitation of platycodin D in biological matrices
The UHPLC/MS-MS was an ultimate 3000 series UHPLC system (Dionex, Genmany) consisting of a quaternary pump, an autosampler, a vaccum degasser, and thermostatically controlled column apartment equipped with thermo scientific quantum vantage™ mass spectrometer system (Thermo-Fisher Scientific, Bremen, Germany), including a hybrid triple quadrupole linear ion trap mass spectrometer coupled with an electrospray Ionization (ESI) source. All data were analyzed by Xcalibur Software (Thermo Fisher Scientific, SanJose, USA) from Thermo-Fisher Scientific. PD and IS were monitored in the negative mode (ESI). High-purity nitrogen was used as sheath gas (45 arb) and auxiliary gas (25 arb) respectively. High-purity argon was used as the collision gas (1.5 mTorr). spray voltage, 3.0 kV; capillary temperature, 350°C; vaporizer temperature, 450°C. Q1 and Q3 quadrupoles were set at unit resolution. The quantification was performed by selected reaction monitoring of the transitions of m/z 1223.5→681.5 for PD, and m/z 609.2 → 301.1 for hesperidins (IS) respectively. The chromatographic analysis was achieved on a hypersil gold column (100 mm × 2.1 mm i.d., 1.9 μm particle size; Thermo, USA). The mobile phase consisted of 0.05% formic acid in water (A) and acetonitrile (B) at a flow rate of 0.4 mL/min. The UHPLC gradient system began with 15% B at 0-1 min, 15-60% B at 1-5 min, 60-100% B at 5-6 min. The column temperature was maintained at 40°C, while the sample-tray temperature was kept at 4°C.
The method had linear calibration curves over the concentrations of 1.95-1500.0 ng/mL for PD in rat plasma, 1.47-1500 ng/mL in HBSS buffer and 1.47-1500 ng/mL in inactivated fecal lysate solution. The extraction recoveries were 74.3-86.6%, 101.3-104.8% and 94.4-97.5% for PD in rat plasma, HBSS buffer and inactivated fecal lysate solution respectively. The lower limit of quantification for PD was 1.95 ng/mL in rat plasma, 1.47 ng/mL in HBSS buffer and 1.47 ng/mL in inactivated fecal lysate solution, respectively. The intra and inter-batch precision and accuracy were <20% for all quality control samples in rat plasma, transport buffer and fecal lysate solution.
The data in this paper were presented as mean tedt for each group, if not specified otherwise. Significance was assessed by one way analysis of variance and Student's t-test. A P value of < 0.05 was considered statistically significant.
| Results and discussion|| |
Oral pharmacokinetics of platycodin D in rats
The plasma concentrations of PD in rats were determined after following oral administration of single PD at 20 mg/kg and equivalent dose of PRE. The results [Figure 2] and [Table 1] showed that single PD was rapidly absorbed into the circulatory system and reached its peak concentration. PD was detected in rat plasma at 10 min after oral administration of single PD and PRE, and reached Cmax at approximately 30 min and 75 min with Cmax approximately 44.45 ng/mL and 17.94 ng/mL, respectively. The AUC (0-?)∞) of PD in rats receiving the single PD was low (73.00 ± 24.17 ng h/mL), which was consistent with the previous results. , The AUC (0-∞) of PD after an equivalent dose of PRE to rats was observed to 96.06 ± 48.51ng h /mL, which was significantly higher than that in rats receiving the single PD, indicating PD in PRE is more exposed to blood circulation than single PD. MRT describes the average time for all the drug molecules to reside in the body. MRT (0-t) of PD was also increased from 1.38 ± 0.20 h (single PD) to 6.10 ± 1.03 (PD in PRE), which showed PD in PRE duration in vivo prolonged, compared to single PD. Previously, Zhan et al., reported the pharmacokinetics of PD between in monomer PD and in PRE. There were some differences between the previous report and our study, which may be attributed to the different doses to rats. In Zhan's study, the oral dosage of single PD and PRE was 80mg/kg and 18.75 g/kg respectively, while the oral dosage was 20 mg/kg and 10 g/kg (corresponding equivalent PD) in our present study. The appearance indicated that the other ingredients contained in PRE, like saponins, may influence the absorption or metabolism of PD.
|Figure 2: Mean concentration-time profiles of platycodin D in rat plasma after oral administration of Platycodi radix extract (10 g/kg) and single platycodin D (20 mg/kg) (mean ± standard deviation, n = 6)|
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|Table 1: Pharmacokinetic parameters of PD in rats following oral administration of PRE (10 g/kg) and single PD (20 mg/kg) (mean±SD, n=6) |
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Transcellular transport of platycodin D across Caco-2 cell monolayer
We determined the apparent permeability of PD both in PRE and in monomer PD in Caco-2 cell monolayers, a model employed to mimic human intestinal absorption characteristics. , Transport of 0.45 μg/mL PD and PRE (200 μg/mL, equivalent to 0.45 μg/mL PD) from apical side to basolateral side in Caco-2 cells were determined within 2 h to understand whether the coexisting components in PRE could influence the transport of PD.
The result of 3-(4, 5-Dimethylthiazol-2-yl)-2, 5-diphenyltetrazolium bromide assay showed that single PD and PRE at the working concentrations had no toxicity on Caco-2 cells within 2 h. The TEER values (>300 Ωcm 2 ) were not different significantly before and after the transport experiment. The results showed that the permeability of PD in monomer and in PRE was 3.52×10−7 cm/s and 2.11×10−7 cm/s respectively, corresponding to incomplete absorption in humans (1×10−6 cm/s),  which indicated that PD, like a lot of saponins, was poorly permeable.  PD in PRE also exhibited poor permeability but a little lower than that of in monomer PD, which implied that the coexisting components in PRE could affect the transport of PD. A lot of other platycodins in PRE may competitively inhibit the transport of PD from apical side to basolateral side. Transcellular transport across Caco-2 cell monolayer declared that the absorption did not result in the phenomenon that higher level of PD exposure in PRE than single PD.
Hydrolysis of platycodin D in fecal lysate
The result of in vitro hydrolysis study of PD by rat fecal lysate was presented in [Figure 3]. PD was hydrolyzed rapidly in fecal lysate, and decreased by 64% within 30 min. The intensity of hydrolyzation slightly diminished and the concentration of PD plateaued around 2 h, only about 20% PD presented at this time point. There are two unbranched sugar chains attached to the carbons C-3 and C-28 in the aglycones in PD, and each chain is composed of one (C-3) and four monosaccharide (C-28) residues. In intestinal bacteria, the major pathway of metabolism of PD is the hydrolysis of C-3 glycoside, followed by acetylation at the multi-site or, alternatively, further hydrolysis at the C-28 oligosaccharide and dehydroxylation of the alglycone part. , Furthermore, we are identifying the intestinal bacteria, such as β-glucosidases, potentially responsible for this metabolism to facilitate future metabolic studies of PD.
|Figure 3: Metabolic profile of platycodin D from single platycodin D (1000 ng/mL) and Platycodi radix extract solution (0.5 mg/mL, corresponding equivalent platycodin D) in rat fecal lysate (mean ± standard deviation, n = 3)|
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Be similar to single PD, PD in PRE was hydrolyzed immediately in a remarkably short time (30 min), about 30% PD disappeared. However, the concentration of PD increased slightly within 1-4 h, and then the hydrolyzation eased step by step. The residue of PD in PRE was more about 1.6 fold than free PD in fecal lysate within 48 h. This pattern of distinctive hydrolysis in fecal lysate between single PD and PD in PRE, to a large extent accounted for their difference of pharmacokinetics. In PRE, there are many platycodins, like PD, such as PD 2, PD 3, and platycoside E. All these platycosides can be defined as bidesmosidic oleanane-type triterpenes with two sugar moieties: A glucose unit attached through an ether linkage at C-3 of a triterpene, and the other embracing arabinose, rhamnose, and xylose in sequence with attachment of a glycoside linkage between C-28 and arabinose.  These bidesmosidic saponins can be easily transformed into second platycodins by alkaline hydrolysis or intestinal microflora. So the other platycodins of PRE may be deglycosylated to PD under the microbial hydrolysis, which accounted for the concentration of PD in PRE increased slightly within 1-4 h. The biotransformation and metabolic profile of plentiful platycodins by intestinal microflora using high resolution mass spectrometry will be further investigated.
| Conclusion|| |
In summary, the pharmacokinetics, intestinal absorption and microbial metabolism of PD both in monomer and in PRE have been studied. The transmembrane behavior of PD was investigated by Caco-2 cells, showed it could not be absorbed well in intestine. It was demonstrated that the distinctive hydrolysis, not absorption, was the main reason for their difference of pharmacokinetics. Better understanding of the interactions between PD and the coexisting platycodins in the PRE will be investigated for further development of Platycodi Radix resources.
| Acknowledgements|| |
This research is supported financially by the National Natural Science Foundation of China (81001499).
| References|| |
State Pharmacopoeia Commission of PR China. Pharmacopoeia of the People's Republic of China. Vol. 1. Beijing, China: Chemical Industry Press; 2010. p. 259-60.
World Health Organization. WHO monographs on selected medicinal plants. Geneva: WHO; 1999. p. 213-20.
Fu WW, Dou DQ, Shimizu N, Takeda T, Pei YH, Chen YJ. Studies on chemical constituents from the roots of Platycodon grandiflorum
. J Nat Med 2006;60:68-72.
Guo L, Zhang C, Li L, Xiao YQ. Advances in studies on Platycodon grandiflorum
. Zhongguo Zhong Yao Za Zhi 2007;32:181-6.
Na YC, Ha YW, Kim YS, Kim KJ. Structural analysis of platycosides in Platycodi radix
by liquid chromatography/electrospray ionization-tandem mass spectrometry. J Chromatogr A 2008;1189:467-75.
Zou JS, Shan JJ, Xie T, Xu JY, Di LQ, Wang SC. Research advances of platycodin D. Chin Tradit Pat Med 2014;36:823-7.
Ahn KS, Noh EJ, Zhao HL, Jung SH, Kang SS, Kim YS. Inhibition of inducible nitric oxide synthase and cyclooxygenase II by Platycodon grandiflorum
saponins via suppression of nuclear factor-kappaB activation in RAW 264.7 cells. Life Sci 2005;76:2315-28.
Kim JY, Hwang YP, Kim DH, Han EH, Chung YC, Roh SH, et al.
Inhibitory effect of the saponins derived from roots of Platycodon grandiflorum
on carrageenan-induced inflammation. Biosci Biotechnol Biochem 2006;70:858-64.
Zhao HL, Sim JS, Shim SH, Ha YW, Kang SS, Kim YS. Antiobese and hypolipidemic effects of platycodin saponins in diet-induced obese rats: Evidences for lipase inhibition and calorie intake restriction. Int J Obes (Lond) 2005;29:983-90.
Zhao HL, Harding SV, Marinangeli CP, Kim YS, Jones PJ. Hypocholesterolemic and anti-obesity effects of saponins from Platycodon grandiflorum
in hamsters fed atherogenic diets. J Food Sci 2008;73:H195-200.
Shin CY, Lee WJ, Lee EB, Choi EY, Ko KH. Platycodin D and D3 increase airway mucin release in vivo
and in vitro
in rats and hamsters. Planta Med 2002;68:221-5.
Lee KJ, Choi CY, Chung YC, Kim YS, Ryu SY, Roh SH, et al.
Protective effect of saponins derived from roots of Platycodon grandiflorum
on tert-butyl hydroperoxide-induced oxidative hepatotoxicity. Toxicol Lett 2004;147:271-82.
Kim MO, Moon DO, Choi YH, Shin DY, Kang HS, Choi BT, et al.
Platycodin D induces apoptosis and decreases telomerase activity in human leukemia cells. Cancer Lett 2008;261:98-107.
Shin DY, Kim GY, Li W, Choi BT, Kim ND, Kang HS, et al.
Implication of intracellular ROS formation, caspase-3 activation and Egr-1 induction in platycodon D-induced apoptosis of U937 human leukemia cells. Biomed Pharmacother 2009;63:86-94.
Chun J, Joo EJ, Kang M, Kim YS. Platycodin D induces anoikis and caspase-mediated apoptosis via p38 MAPK in AGS human gastric cancer cells. J Cell Biochem 2013;114:456-70.
Pei L, Bao Y, Ma L, Wang Q, Ye Y, Han X, et al.
A sensitive method for determination of platycodin d in rat plasma using liquid chromatography/tandem mass spectrometry and its application to a pharmacokinetic study. Planta Med 2012;78:244-51.
Kim TH, Lee BE, Kim EJ, Choi YS, Lee KS, Kim HR, et al.
Determination of platycodin D and platycodin D3 in rat plasma using liquid chromatography-tandem mass spectrometry. Scientific World Journal 2014;2014:231293.
Zhan Q, Zhang F, Gao SH, Cai F, Jiang B, Sun LN, et al.
An HPLC-MS/MS method for the quantitative determination of platycodin D in rat plasma and its application to the pharmacokinetics of Platycodi radix
extract. Chin J Nat Med 2014;12:154-60.
Zhou W, Zhu XX, Yin AL, Cai BC, Wang HD, Di L, et al.
Effect of various absorption enhancers based on tight junctions on the intestinal absorption of forsythoside A in Shuang-Huang-Lian, application to its antivirus activity. Pharmacogn Mag 2014;10:9-17.
Niu T, Smith DL, Yang Z, Gao S, Yin T, Jiang ZH, et al.
Bioactivity and bioavailability of ginsenosides are dependent on the glycosidase activities of the A/J mouse intestinal microbiome defined by pyrosequencing. Pharm Res 2013;30:836-46.
Artursson P, Karlsson J. Correlation between oral drug absorption in humans and apparent drug permeability coefficients in human intestinal epithelial (Caco-2) cells. Biochem Biophys Res Commun 1991;175:880-5.
Hu M, Chen J, Zhu Y, Dantzig AH, Stratford RE Jr, Kuhfeld MT. Mechanism and kinetics of transcellular transport of a new beta-lactam antibiotic loracarbef across an intestinal epithelial membrane model system (Caco-2). Pharm Res 1994;11:1405-13.
Yu K, Chen F, Li C. Absorption, disposition, and pharmacokinetics of saponins from Chinese medicinal herbs: What do we know and what do we need to know more? Curr Drug Metab 2012;13:577-98.
Ha YW, Na YC, Ha IJ, Kim DH, Kim YS. Liquid chromatography/mass spectrometry-based structural analysis of new platycoside metabolites transformed by human intestinal bacteria. J Pharm Biomed Anal 2010;51:202-9.
Jeong EK, Ha IJ, Kim YS, Na YC. Glycosylated platycosides: Identification by enzymatic hydrolysis and structural determination by LC-MS/MS. J Sep Sci 2014;37:61-8.
[Figure 1], [Figure 2], [Figure 3]
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| ||International Journal of Immunopathology and Pharmacology. 2016; 29(4): 696 |
|[Pubmed] | [DOI]|