Differential systemic exposure to galangin after oral and intravenous administration to rats
- Feng Chen†1,
- Yin-Feng Tan†1,
- Hai-Long Li1,
- Zhen-Miao Qin1,
- Hong-Die Cai1, 2,
- Wei-Yong Lai1,
- Xiao-Po Zhang1,
- Yong-Hui Li1,
- Wei-Wei Guan1,
- You-Bin Li1Email author and
- Jun-Qing Zhang1Email author
© Chen et al.; licensee BioMed Central. 2015
Received: 12 October 2014
Accepted: 12 March 2015
Published: 31 March 2015
Galangin (3,5,7-trihydroxyflavone) is present in high concentrations in herbal medicine such as Alpinia officinarum Hance. Galangin shows multifaceted in vitro and in vivo biological activities. The number and position of hydroxyl groups in this molecule play an important role in these biological activities. However, these hydroxyl groups undergo glucuronidation and sulfation in in vitro assay system. However, the systemic exposure to galangin after dosing in animals and/or humans remains largely unknown. Thus it is not clear whether the galangin exists in the body at concentrations high enough for the biological effects. Furthermore, the metabolite identification and the corresponding plasma pharmacokinetics need to be characterized.
Two LC-MS/MS methods were developed and validated and successfully applied to analyze the parent drug molecules and aglycones liberated from plasma samples via β-glucuronidase hydrolysis. Our major findings were as follows: (1) The routes of administration showed significant influences on the systemic exposure of galangin and its metabolites. (2) Galangin was preferentially glucuronidated after p.o. dosing but sulfated after i.v. medication. (3) Kaempferol conjugates were detected demonstrating that oxidation reaction occurred; however, both glucuronidation and sulfation were more efficient. (4) Oral bioavailability of free parent galangin was very low.
Systemic exposure to galangin and its metabolites was different in rat plasma between oral and intravenous administration. Further research is needed to characterize the structures of galangin conjugates and to evaluate the biological activities of these metabolites.
Flavonoids constitute the most ubiquitous polyphenolic compounds in the human dietary sources (e.g. fruits, vegetables, tea and wine) and herbal medicines. Epidemiological studies suggest an inverse association between flavonoids intake and risks for certain disease such as cardiovascular and neurodegenerative disease and certain human cancers [1-3]. These beneficial roles are closely associated with their antioxidative activities, cardiovascular protection, neuroprotection, anti-inflammation and/or antitumor effects. Obviously, a majority of pharmacological assessments have been performed on the flavonoid aglycones (e.g., quercetin, kaemfperol) . However, flavonoids, once ingested, undergo extensive presystemic metabolism by methylation, glucuronidation and sulfation in the intestine and in the liver, resulting in very low concentration localizing in the body in its original form . Therefore, accurate and complete pharmacokinetic (PK) information of flavonoid is useful for the pharmacological activity evaluation of unmetabolized chemicals and/or phase II conjugates substantially circulating in the bloodstream after dosing, which may enhance understanding of the final chemical entities that reach the target sites.
Oral administration of galangin (20 mg/kg) efficiently counteracted the anomalies induced by benzo(a)pyrene in male Swiss albino mice via the increased activity of phase I drug metabolic enzymes, lipid peroxidation levels, tissue marker enzymes and the decreased activity of phase II metabolic enzymes, antioxidant levels, as well as severe alveolar and bronchiolar damages and restored cellular homeostasis . Intraperitoneal injection of galangin (5 and 15 mg/kg) to BALB/c mice dose-dependently inhibited ovalbumin-induced increases in total cell counts, eosinophil counts and IL-4, IL-5, IL-13 levels in bronchoalveolar lavage fluid and reduced the ovalbumin-specific IgE in serum. Galangin blocked κB degradation, phosphorylation of the p65 subunit of NF-κB and p65 nuclear translocation from lung tissues of ovalbumin-sensitized mice . Overall, in vivo pharmacological studies have also confirmed that galangin has a plethora of beneficial biological effects. However, the systemic exposure to galangin after dosing in animals and/or humans remains largely unknown. Since galangin undergoes extensive phase II metabolism, it is not clear which species among galangin and its metabolites is mainly responsible for the observed in vivo pharmacological effects. To answer this question, it is necessary to characterize the pharmacokinetic behaviors of galangin and its metabolites.
The primary objective of this study was to identify galangin metabolites in rat plasma after oral (p.o.) and intravenous (i.v.) administration of galangin solution. Also, we investigated the pharmacokinetic behaviors of galangin and its metabolites after different routes of administration.
Chemicals and materials
Analytical reference standards of galangin, kaempherol and quercetin (Figure 1) were obtained from the National Institutes for Food and Drug Control (Beijing, China). Chrysin (used as internal standard, IS; Figure 1) was separated from Alpinia oxyphylla and identified in our lab. For galangin, kaempherol, quercetin, and chrysin, the purity is over 98.0%. L-Ascorbic acid (Vitamin C) was obtained from Biosharp Co. (Hefei, China). β-Glucuronidase (Type HP-2, from Helix pomotia, containing ≥ 100,000 unit/mL of β-glucuronidase and 7,500 unit/mL of sulfatase) was purchased from Sigma-Aldrich (St. Louis, MO, USA). Methanol and acetonitrile for HPLC use were products of Tedia Company Inc. (Fairfield, OH, USA). HPLC-grade formic acid (HCOOH) was purchased from Aladdin Industrial Inc. (Shanghai, China). Purified water was prepared in house using the Milipore system (Millipore, Bedford, MA, USA). The other chemical reagents of analytical grade or better were obtained from Hainan YiGao Instrument Co., Ltd (Haikou, China).
The use of rats and study protocols were approved by the Institutional Animal Care and Use Committee at the Hainan Medical University (Haikou, China). Female Sprague-Dawley (SD) rats (204–248 g) were purchased from DongChuang Laboratory Animal Service Department (Changsha, China). Commercial rat chow was available ad libitum except for an overnight fasting period before dosing. All rats had free access to water.
Drug administration and blood collection
For the p.o. and i.v. administration, galangin solution (1 mg/mL) was dissolved in a mixture containing 6% (v/v) PEG400, 9.8% (w/v) Tween-80 and 4.4% (v/v) ethanol. The rats were randomly divided into two groups (3 rats/group) to receive oral (10 mg/kg) administration and intravenous (2 mg/kg) administration of galangin, respectively. Serial blood samples (0.3 mL; 0, 5, 15, 30 min and 1, 2, 4, 6, 8, 10 and 24 h post dosing) were collected into heparinized tubes. The blood samples were then centrifuged at 13,000 rpm for 10 min and the plasma fractions were decanted and frozen at –70°C until analysis.
Plasma sample clean-up
The rat plasma samples were treated via different methods for qualitative and quantitative analysis, respectively. The details were as follows:
For identification of galangin and its metabolites (qualitative analysis), 20 μL of each plasma sample collected at different time points (5, 15, 30 min and 1, 2 h) in the same group were pooled together. The resultant mixture (100 μL) was treated via vortex-shaking for 10 min with 300 μL methanol and then centrifuged at 13,000 rpm for 10 min. The upper supernatant (~390 μL) was dried under a stream of N2 via a Techne™ Sample Concentrator (Bibby Scientific Ltd., Staffordshire, UK). The residue was reconstituted in 50 μL of methanol, centrifuged ditto, and 10 μL of the resulting supernatant was applied for LC-MS/MS analysis.
For the quantification of free galangin, as well as aglycones liberated from its glucuronidated metabolites, aliquot (50 μL) of each plasma sample was precipitated with 150 μL of the IS-spiked acetonitrile solution (500 ng/mL). The mixture was vortex-shaked for 5 min and centrifuged at 13,000 rpm for 10 min. The resulting supernatant (10 μL) was directly applied for LC–MS/MS analysis.
Enzymatic hydrolysis coupled with protein precipitation 
Aliquots (50 μL) were treated with 150 μL of β-glucuronidase (2,000 unit/mL in pH 5 acetate buffer). 10 μL of ascorbic acid (1 mg/mL) was added and incubated at 37°C for 60 min. After incubation, the above plasma sample was mixed with 150 μL of acetonitrile containing the IS (500 ng/mL) and then vortex-extracted for 5 min and centrifuged at 18,140 g for 10 min. Ten microliters of the resulting supernatant were directly injected into LC–MS/MS system for analysis.
The LC-MS/MS system consisted of an AB-SCIEX API 4000 plus triple quadrupole mass spectrometer (Toronto, Canada) interfaced via ionization probe with a Shimadzu Prominence ultra fast liquid chromatography chromatographic system (Kyoto, Japan) including two pumps, a degasser unit, an auto-sampler and a column oven. The AB-SCIEX Analyst software packages were used for controlling the LC-MS/MS system, data acquisition and processing.
Identification of galangin and its metabolites in rat plasma
Chromatographic separations were achieved on a 4-μm Phenomenex Synergi Fusion-RP C18 column (2.0 mm i.d. × 50 mm) under 40°C with a pre-column 0.5-μm biocompatible inline filter. The mobile phase (delivered at 0.30 mL/min) was methanol/H2O containing 0.1‰ formic acid with a gradient program as follows: from 0% B to 2% B in 0.01 min, hold for 1 min; from 2% B to 35% B in 0.01 min, hold for 3 min; from 35% B to 90% B in 11 min; back to 2% B in 0.01 min; maintain 4.99 min .
The mass spectrometer was operated in the negative electrospray ionization (ESI) mode with selected multiple reaction monitoring (MRM) mode for all the analytes. The precursor-to-product ion pairs used for galangin, quercetin and kaempferol were m/z 268.9 → 108.0, 300.9 → 150.9 and 285.0 → 93.0, respectively, with a scan times of 20 ms for each ion pair. The phase II metabolites of galangin were also measured. The precursor-to-product ion pairs used for glucuronidated galangin (M_Gal-G), galangin diglucuronide (M_Gal-2G), galangin triglucuronide (M_Gal-3G), sulfated galangin glucuronide (M-Gal-G-S), sulfated galangin (M_Gal-S), galangin disulfate (M_Gal-2S), galangin trisulfate (M_Gal-3S), sulfated galangin diglucuronide (M-Gal-2G-S), disulfated galangin glucuronide (M-Gal-G-2S), methylated galangin (M-Gal-CH3), glucuronidated kaempferol (M_KMF-G), kaempferol diglucuronide (M_KMF-2G), sulfated kaempferol glucuronide (M_KMF-G-S), sulfated kaempferol (M_KMF-S), disulfated kaempferol (M_KMF-2S), glucuronidated quercetin (M_QCT-G), quercetin diglucuronide (M_QCT-2G), sulfated quercetin glucuronide (M_QCT-G-S), sulfated quercetin (M_QCT-S) and disulfated quercetin (M_QCT-2S) were m/z 444.9 → 268.9, 620.9 → 268.9, 796.9 → 268.9, 524.9 → 268.9, 348.9 → 268.9, 428.9 → 268.9, 508.9 → 268.9, 700.9 → 268.9, 604.9 → 268.9, 282.9 → 108.0, 461.0 → 285.0, 637.0 → 285.0, 541.0 → 285.0, 365.0 → 285.0, 445.0 → 285.0, 476.9 → 300.9, 652.9 → 300.9, 556.9 → 300.9, 380.9 → 300.9 and 460.9 → 300.9, respectively.
Quantitative analysis of free and total galangin in rat plasma
Chromatographic separations of prepared samples were achieved using a Phenomenex Kinetex 2.6 μm XB-C18 column (2.10 mm i.d × 50 mm) maintained at 40°C and coupled with a 0.5-μm biocompatible inline filter. The LC mobile phase composition and flow rate were the same as the above-mentioned. The gradient program was as follows: 0–0.3 min at 1% B; from 1% B to 100% B in 0.01 min (0.31 min) and maintained 2.7 min (0.31–3 min); from 100% B to 1% B in 0.01 min (3.01 min) and maintained 1 min (3.01–4 min). The mass spectrometer was operated in the negative ion ESI mode with MRM for galangin, M_Gal-G and IS. The precursor-to-product ion pairs used for galangin, M_Gal-G and chrysin were m/z 268.9 → 108.0, 444.9 → 268.9 and 253.0 → 142.9, respectively, with a scan time of 40 ms for each ion pair.
Assay validation was performed according to the US FDA guidance on bioanalytical method validation (http://www.fda.gov/downloads/Drugs/Guidances/ucm070107.pdf). The quality control samples were prepared from an independent weighing of the reference standard.
To determine the PK parameters, the concentration-time data were estimated by a non-compartmental method using the Kinetica 2000 software package (version 3.0; Innaphase Corp., Philadelphia, PA, USA). The C max and T max were observed values with no interpolation. The area under concentration-time curve up to the last measured time point (AUC0→t) was calculated by the trapezoidal rule method. The AUC0→∞ was generated by extrapolating the AUC0→t to infinity. Results are expressed as the mean ± SD.
Results and discussion
Phase II conjugation metabolites of galangin in rat plasma
Our results revealed that the oxidized products of galangin (kaempferol and quercetin) were not measurable in the rat plasma samples (Figure 1). Also the glucuronides, diglucuronide, sulfated metabolites and sulfated diglucuronide metabolites of quercetin could not be detected. However, we found the occurrence of glucuronidated and sulfated quercetin in rat bile and urine samples after a single p.o. or i.v. administration of galangin solution to rats (data not shown). The phase II conjugation metabolites of kaempferol including glucuronide (Rt 7.66 min) and diglucuronide (Rt 11.42 and 11.89 min) could be detected (Figure 2). Overall, the major metabolites of galangin in rat plasma were glucuronides and sulfates; meanwhile, trace amounts of kaempferol phase II conjugates were also detected.
Plasma pharmacokinetics of galangin
We have identified two galangin glucuronides in rat plasma; unfortunately there are no well-established standards for their quantification analysis. In this study, alternatively, free type and hydrolyzed type of galangin in rat plasma were detected using different plasma sample clean-up methods, i.e., acetonitrile precipitation and with or without enzyme hydrolysis. In order to enhance analysis efficiency, a 4-min “pulse gradient” program was applied to analyze galangin and its glucuronidated metabolites. Because the run time was shortened from 20 min to 4 min, the two galangin glucuronides could not be separated; but formed a single peak (Rt 2.01 min) abutting the parent drug (Rt 2.10 min).
Method validation results
The calibration curve (Y = 0.000177X + 1.47 × 10-5, weight coefficient 1/×2) was linear over the measured range of 2-2000 ng/mL for free type of galangin with correlation coefficient of 0.994. The LLOQ, precision and accuracy was 2 ng/mL, 9.18% and 101%, respectively. Similar results were obtained for the quantification of galangin in samples after the treatment of β-glucuronidase hydrolysis. The LLOQ was 2 ng/mL, with a precision of 11.4% and accuracy of 102% for this compound.
Precision and accuracy of the galangin in rat plasma (n = 5)
Spiked concentration (ng/mL)
14.6 ± 8.19
14.5 ± 1.29
625 ± 40.0
610 ± 36.6
1292 ± 39.6
1219 ± 87.0
Matrix effect and extraction recovery of galangin and IS in rat plasma (n = 5)
Peak area (× 10 3 )
Mean ± SD
Mean ± SD
Mean ± SD
3.44 ± 0.39
2.98 ± 0.08
1.04 ± 0.11
97.0 ± 5.14
86.5 ± 4.48
37.8 ± 1.62
168 ± 16.0
147 ± 5.37
76.0 ± 3.14
279 ± 35.4
251 ± 9.52
80.0 ± 5.24
Stability of the galangin in rat plasma (n = 5)
Spiked concentration (ng/mL)
Short-term stability (4 h at room temperature)
Autosampler stability (12 h at room temperature)
Freeze-thaw stability (3 cycles)
Mean ± SD
Mean ± SD
Mean ± SD
15.1 ± 1.9 (12.9)
14.5 ± 1.70 (11.7)
15.1 ± 1.5 (10.2)
535 ± 43.2 (8.08)
592 ± 33.2 (5.61)
527 ± 13.9 (2.63)
1070 ± 18.9 (1.76)
1150 ± 52.3 (4.65)
1086 ± 23.2 (2.14)
Systemic exposure to and pharmacokinetics of galangin
Pharmacokinetic data of galangin after administration to rats (n = 3)
Free type of galangin
C max or C 5min (ng/mL)
1456 + 802
219 ± 207
T max (h)
265 ± 176
48.7 ± 44.1
AUC0-∞ (h ng/mL-1)
271 ± 179
80.8 ± 40.5
t 1/2 (h)
0.21 ± 0.02
0.18 ± 0.01
1.28 ± 1.75
CLtot, p (L•h/kg)
6.86 ± 3.32
V ss (L/kg)
1.20 ± 0.55
3.67 ± 3.33
Hydrolyzed type of galangin after enzyme hydrolysis treatment
C max or C 5min (ng/mL)
2273 + 265
5103 ± 829
T max (h)
AUC0-t (h ng/mL)
1169 ± 360
22184 ± 4482
AUC0-∞ (h ng/mL-1)
1188 ± 339
22214 ± 4482
t 1/2 (h)
1.37 ± 0.69
1.19 ± 0.51
4.03 ± 1.09
CLtot, p (L•h/kg)
1.59 ± 0.47
V ss (L/kg)
1.73 ± 0.42
380 ± 77
The routes of administration demonstrated significant influences on the systemic exposure to the galangin and its metabolites. Given that the positive pharmacological activities confirmed via in vitro and in vivo studies, it remains open to question what exactly makes them run. The premise is that enough free parent drug molecules could reach the certain target when galangin works as active principle. Under this situation, there should be a dynamic equilibrium of galangin between systemic circulation and certain targets. Conjugated galangin circulates in the bloodstream and transforms into aglycone before arriving at the targets. Mukai et al. found that quercetin glucuronide could be deconjugated to quercetin by microglial MG-6 cells . As for galangin, further studies on tissue and cellular distribution should be done in the future in order to test the hypothesis. On the other hand, the galangin glucuronides and sulfates could work as active principle and play a critical role in the claimed activities. Some studies have confirmed that the quercetin glucuronides have various pharmacological roles, including anti-inflammatory effects [22,23], anti-atherosclerotic roles [24-26], immune-modulatory activity , antioxidant effects [28,29] and anti-proliferative effect . Therefore, biological activities of galangin conjugate (chemically synthesized or separated from biosamples) need to be evaluated.
In summary, this study provided direct evidence that the routes of administration show significant influences on the systemic exposure level of galangin and its metabolites. Galangin was preferentially glucuronidated after p.o. dosing but sulfated after i.v. medication. Kaempferol conjugates were measured indicating that oxidation reaction occurred; however, both glucuronidation and sulfation of galangin were more efficient. LC-MS/MS methods were developed and validated for quantification of galangin both in its unmetabolized form and hydrolyzed form liberated from its glucuronides via β-glucuronidase hydrolysis, respectively. The oral bioavailability of parent galangin was very low. Further research is needed to unambiguously identify the structures of galangin conjugates and to evaluate the biological roles of these metabolites.
This work was supported by GrantZDZX2013008-3 and ZDXM 2015078 from the Hainan Science and Technology Major Project, Hainan Special Plan for the Modernization of Chinese Medicines (2015ZY06) Grant HNKY2014-50 from Hainan province colleges and universities projects for educational reform. We are also grateful to Dr. Xiu-xue Li from Shanghai Institute of Materia Medica for screening relevant articles from reference lists.
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