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Ginger extracts have been studied in various clinical trials for different indications. However, the pharmacokinetics of the ginger active constituents in human biological matrices is not well investigated. This study aims to develop a LC-MS/MS method for simultaneous measurement of 6-, 8-, and 10-gingerols and 6-shogaol and study their pharmacokinetics in human plasma and colon tissues. A sensitive LC-MS/MS method was established and validated with a low limit of quantification of 2–5 ng/mL. The intra- and inter-day accuracy ranged from −7.3% to 10.4% and from −9.4% to 9.8%, respectively. The intra- and inter-day precision ranged from 0.9% to 10.9% and from 2.0% to 12.4%, respectively. The glucuronide and sulfate metabolites of 6-, 8-, and 10-gingerols and 6-shogaol in plasma and colon tissues were quantified after hydrolysis with β-glucuronidase and sulfatase. After oral dosing of 2.0 g ginger extracts in human, free 10-gingerol and 6-shogaol were detected in plasma with peak concentrations (9.5±2.2 and 13.6±6.9 ng/mL, respectively) at 1 h after oral administration, but no free 6-gingerol and 8-gingerol were detected in plasma from 0.25 to 24 h. The peak concentrations of glucuronide metabolites of 6-, 8-, and 10-gingerols and 6-shogaol were 0.47±0.31, 0.17±0.14, 0.37±0.19, and 0.73±0.54 μg/mL at 1 h, respectively. The peak concentrations of the sulfate metabolites of 6-, 8-, and 10-gingerols and 6-shogaol were 0.28±0.15, 0.027±0.018, 0.018±0.006, and 0.047±0.035 μg/mL at 1 h, respectively. Very low concentrations (2–3 ng/mL) of 10-gingerol glucuronide and sulfate were found in colon tissues. Pharmacokinetic analysis showed that half-lives of these four analytes and their metabolites were 1–3 h in human plasma. No accumulation was observed for 6-, 8-, and 10-gingerols and 6-shogaol and their metabolites in both plasma and colon tissues after multiple daily dosing.
The antioxidative, anti-inflammatory, and antitumor properties of ginger (Zingiber officinale Roscoe, Zingiberaceae) have been reported in previous studies (1–5). Various clinical trials have evaluated ginger extracts to decrease lipid levels (6), treat arthritis (7,8), prevent nausea and vomiting (9–11), and reduce pain in women with primary dysmenorrhea (12). However, clinical studies using ginger extracts produced mixed or moderate/marginal benefits. For instance, Chaiyakunapruk et al. (13) demonstrated that administration of ginger at a dose of 1 g was more effective than placebo for the prevention of postoperative nausea and vomiting and postoperative vomiting. In contrast, Betz et al. (14) concluded that there was no clear evidence for the efficacy of ginger in the treatment of postoperative nausea and vomiting and of kinetosis. Bliddal et al. (15) showed that 170-mg daily dosing for 3 weeks of ginger powder did not show significant benefit over placebo in relieving pain in patients with osteoarthritis. Hoewever, a 6-week treatment with 510 mg of ginger extract daily dosing produced moderate effect on reducing pain in the knee in patients with osteoarthritis (16).
Ginger contains volatile oils (~1% to 3%) and non-volatile pungent components oleoresin (1). A variety of active components were identified in the oleoresin of ginger including gingerols and shogaols. Gingerols are a series of homologues with varied unbranched alkyl chain length, whereas shogaols are a series of homologues derived from gingerols with dehydration at the C-5 and C-4 during long-term storage or thermal processing. Other active compounds from the oleoresin portion of ginger were also reported, such as [6]-paradol; [6]- and [10]-dehydrogingerdione; [6]- and [10]-gingerdione; [4]-, [6]-, [8]-, and [10]-gingerdiol; [6]-methylgingerdiol; zingerone; [6]-hydroxyshogaol; [6]-, [8]-, and [10]-dehydroshogaol; and diarylheptanoids (17–19). Among these compounds, gingerols and shogaols are the major constituents of oleoresin, while the other compounds are present in a limited amount, accounting for 1–10% of the overall amount of gingerols and shogaols (19). Gingerols (especially 6-gingerol) are the major components in the fresh ginger rhizome. The amount of shogaols is increased in the dried ginger, as evidenced by the reduction of the ratio of 6-gingerol to 6-shogaol from 10:1 in fresh ginger to 1:1 in dried ginger (17,18,20).
Since ginger extracts contain various components, it would be important to identify which compounds are responsible for their pharmacological effects. It was demonstrated that 6-, 8-, and 10-gingerols and 6-shogaol showed efficacy in anti-inflammatory, antibacterial, antipyretic, antilipidemic, antitumorigenic, and antiangiogenic effects (5,21–27). In addition, 6-gingerol was shown to inhibit leukotriene A4 hydrolase (LTA4H) and suppress anchorage-independent cancer cell growth in colorectal cancer cells (HCT116 and HT29) with IC50's of 50 and 35 μM, respectively (28). Sang et al. (19) demonstrated that 6-, 8-, and 10-shogaols exhibited much higher antiproliferative potency than 6-, 8-, and 10-gingerols against human lung cancer cells (H-1299) with IC50's of 8 μM for 6-shogaol and 150 μM for 6-gingerol. In addition, 10-gingerol was the most potent among the gingerols (19). Furthermore, Dugasani et al. (29) found that 6-shogaol showed the most potent efficacy of antioxidative activity with an IC50 of about 8 μM, while 6, 8, and 10-gingerols had IC50's of 28, 20, and 12 μM, respectively.
In most of the clinical trials, the content of active ingredients in the ginger extract was not measured. The use of non-standardized ginger extracts in different clinical studies partly explain the mixed results of the clinical studies in addition to the different study designs and dose regimens. A study by Schwertner et al. showed that variable amount of 6-gingerol, 6-shogaol, 8-gingerol, and 10-gingerol in various brands of ginger root dietary supplements (7). In these different products, 6-gingerol ranged from 0.00 to 9.43 mg/g, 6-shogaol ranged from 0.16 to 2.18 mg/g, 8-gingerol ranged from 0.00 to 1.10 mg/g, and 10 gingerol ranged from 0.00 to 1.40 mg/g.
Furthermore, despite the numerous studies of the pharmacological effects of the ginger extracts in the human clinical trials, there are limited studies of the pharmacokinetics of the ginger active constituents in human biological matrices. The concentrations of 6-, 8-, and 10-gingerols and 6-shogaol for their efficacy in vivo are still largely unknown. In our previous study, we developed a HPLC method to determine the concentrations of 6-, 8-, and 10-gingerols and 6-shogaol in healthy human subjects who received oral dose of ginger extracts at 2.0 g per day (1). However, due to the low sensitivity of the HPLC method with low limit of quantification (LLOQ) ranging from 0.10 to 0.25 μg/mL for the four analytes, we did not detect any of these four compounds in the plasma, although we detected the glucuronide conjugates of the four analytes. No sulfate conjugates of 8-gingerol, 10-gingerol, and 6-shogaol were detected. Thus, a more sensitive method for the quantification of 6-, 8-, and 10-gingerols and 6-shogaol and their metabolites is desired to characterize the pharmacokinetics of the active ingredients of ginger in human.
In this study, we developed and validated a LC-MS/MS method for the quantification of 6-, 8-, and 10-gingerols and 6-shogaol simultaneously, with the LLOQ ranging from 2 to 5 ng/mL. We further utilized this method to analyze human plasma samples and detected low concentrations of free 10-gingerol and 6-shogaol, while most of the 6-, 8-, and 10-gingerols and 6-shogaol existed in plasma as glucuronide and sulfate metabolites. The pharmacokinetics of 6-, 8-, and 10-gingerols and 6-shogaol and their metabolites were analyzed. The half-lives of all compounds and their metabolites were between 1 and 3 h (Fig. (Fig.11).
The ginger product used in this study was manufactured by Pure Encapsulations® (Sudbury, MA; batch no. ZO/06006). A 250-mg dry extract of ginger root, which contained 6.60 mg (2.64%) 6-gingerol, 1.58 mg (0.63%) 8-gingerol, 3.05 mg (1.22%) 10-gingerol, and 5.63 mg (2.25%) 6-shogaol, was used. β-glucuronidase (type IX-A from Escherichia coli) and sulfatase (type H-1 from Helix pomatia) were purchased from Sigma-Aldrich Inc. Sodium phosphate and sodium acetate (American Chemical Society-certified) were purchased from Fisher Scientific. The 6-, 8-, and 10-gingerols and 6-shogaol were purchased from Chromadex. Pelargonic acid vanillylamide (PAV), the internal standard, was obtained from Sigma. Acetonitrile (HPLC grade) and methanol (HPLC grade) were purchased from Fisher Scientific Co. (Pittsburgh, PA). Formic acid (analytical grade) was from Sigma Chemical Company (St. Louis, MO). Water was purified with a Milli-Q water system (Millipore, Bedford, MA).
Three studies were conducted in healthy volunteers, single dose in normal-risk participants, and multiple doses in normal-risk and high-risk participants. Participants were 18 years or older and in good health as defined by an unremarkable medical history, physical and screening blood work, and no chronic medication use. Exclusion criteria for the study included: anyone with (1) a history of peptic ulcer disease, gastrointestinal bleeding from gastric or duodenal ulcers, or gastrin secreting tumors; (2) pregnant or lactating women; (3) history of cardiovascular disease; (4) lactose intolerance; (5) or an allergy to ginger. Participants were asked to avoid all foods containing ginger within the 14 days prior to drug administration and completed a food checklist to verify that they were not consuming any ginger-rich foods such as ginger ale or Japanese food. All study procedures were performed at the University of Michigan General Clinical Research Center after the participant gave written and informed consent. The study was approved by the University of Michigan Institutional Review Board.
Nine healthy volunteers received 2-g oral dose of the ginger extracts. Blood was drawn from the participants at baseline, 0.25, 0.5, 0.75, 1, 2, 4, 6, 10, 24, 48, and 72 h after ingestion of the ginger extracts. The plasma was separated from blood immediately and kept at −80°C until LC-MS analysis.
Thirty participants were enrolled and recruited. Participants to be eligible were assessed as being at normal risk for developing colorectal cancer. Normal risk was defined as no history of either familial colorectal cancer syndromes or first-degree relatives with colon cancer diagnosed before the age of 60. Normal-risk individuals also could not have a personal history of colorectal cancer or resection of a villous adenoma (>1 cm in size or any adenoma containing carcinoma in situ). Participants were randomized into two different groups. Sixteen patents were given placebo, while 14 patients were given eight 250-mg ginger extract capsules daily for 28 days. Blood was drawn at baseline and within 24 h after the last dose. The plasma was separated from blood immediately and kept at −20°C until assayed.
Participants underwent two flexible sigmoidoscopies, one before drug treatment and the second at 28 days after drug treatment. The second procedure was performed at 24 h after the final ginger dose. The participants were not prepared for the procedure with any enemas.
Each biopsy specimen was taken ~2 cm or more from other biopsy sites in distal sigmoid colonic mucosa that had no visual appearance of trauma or recent biopsy. Biopsy samples were placed into a sterile 1.5-mL Eppendorf tube and frozen in liquid nitrogen. The specimens were stored at −80°C until analysis.
Twenty participants who were at high risk for developing colorectal cancer were registered in the study. Participants were randomized, ten in each group, to receive either eight 250-mg ginger extract capsules or placebo (lactose powder) daily for 28 days. High risk for colorectal cancer was defined as having a first-degree relative diagnosed with colon rectal cancer before the age of 60, and/or a prior history of a colon adenoma, and/or resected early (Dukes A, B, or C) colon cancer previously.
The quantitative LC-MS/MS analysis was performed on an API 3200 hybrid triple quadrupole/linear ion trap mass spectrometer coupled with an Agilent 1200 HPLC system (Applied Biosystems, MDS Sciex Toronto, Canada).
The chromatography was performed using a 1.8-μm Agilent Zorbax StableBond-C18 column (4.6×50-mm i.d.). The injection volume was 10 μL and the flow rate was 300 μL/min. Mobile phase A and B were water containing 0.1% formic acid (v/v) and ACN, respectively. The flow gradient was initially at 38:62 (v/v) of A/B for 3 min, linearly ramped to 0:100 over 1.5 min, held at 0:100 for 3.4 min, and then returned to 38:62 for 0.1 min. This condition was held for a further 5 min prior to the injection of another sample.
The mass spectrometer was operated at ESI positive ion mode and detection of the ions was performed in the multiple reaction monitoring (MRM) mode. The analytes and internal standard (IS) were first characterized by Q1 MS (Q1) scan and enhanced product ion (EPI) scan to determine the precursor ions and product ions used in MRM mode. Figure 2 shows the EPI spectra of the analytes and IS. The MS/MS transitions were: 6-gingerol, m/z 295.2 precursor ion [M+H]+ to the m/z 137.1 product ion; 8-gingerol, m/z 323.2 precursor ion [M+H]+ to the m/z 137.1 product ion; 10-gingerol, m/z 351.2 precursor ion [M+H]+ to the m/z 137.1 product ion; 6-shogaol, m/z 277.2 precursor ion [M+H]+ to the m/z 137.1 product ion; IS, m/z 294.2 precursor ion [M+H]+ to the m/z 137.1 product ion. The ion spray voltage was set at 5,000 V, ionization temperature set as 400°C, CAD was set as medium, and Ihe was set as OFF. The instrument parameters and curtain gas, gas 1 and gas 2 (auxillary gas), were set at 10, 60, and 40, respectively. Compound parameters, declustering potential, collision energy, entrance potential, collision entrance energy, and collision exit potential were 33, 27, 5, 18.4, and 2 V for 6-gingerol; 33, 27, 5,19.19, and 2 V for 8-gingerol; 33, 27, 5, 19.97, and 2 V for 10-gingerol; 44, 18, 5, 17.9, and 2 V for 6-shogaol; and 33, 27, 5, 18.38, and 2 V for internal standard PAV, respectively. Data acquisition and quantitation were performed using analyst software version 1.4.2 (Applied Biosystems, MDS Sciex Toronto).
The stock solutions of 6-, 8-, and 10-gingerols, 6-shogaol, and PAV were prepared in methanol with concentrations of 1 mg/mL. A series of working standard of analyte mixture containing 0.04, 0.1, 0.2, 0.4, 1, 2, 4, 10, and 40 μg/mL of the four analytes was prepared by dilution from the stock solutions with methanol. Internal standard PAV working solution was prepared by diluting the stock solution with methanol to the final concentration of 2 μg/mL. Low, medium, and high concentration quality control working stock solutions (0.3, 5, and 20 μg/mL) were prepared in methanol using separately weighed stock solutions of the four analytes. Nine calibration standard solutions at 0.002, 0.005, 0.01, 0.02, 0.05, 0.1, 0.2, 0.5, and 2 μg/mL were prepared by spiking blank plasma with appropriate amounts of working standards. QC plasma samples at 0.015, 0.25, and 1 μg/mL were prepared in the same way as the calibration standard. Blank plasma sample without analytes and internal standard and zero plasma samples with internal standard but no analytes were also prepared and analyzed. All the standard solutions were stored at 4°C.
Plasma samples (100 μL) were transferred to microcentrifuge tubes. Then, 5 μL internal standard PAV working solution (2 μg/mL) was added to the plasma; the mixture was added with 295 μL ACN and vortexed for 1 min at high speed. The tubes were centrifuged at 13,000 rpm for 10 min to precipitate protein. The supernatants were transferred to vial inserts and 10 μL was injected into LC-MS/MS.
To analyze the metabolic conjugates (glucuronide and sulfate) of 6-, 8-, and 10-gingerols and 6-shogaol, the plasma samples were pre-incubated with β-glucuronidase and sulfatase as described previously (1,30). The total concentrations of the gingerols and shaogaol with separate enzyme hydrolysis were comparable to those with hydrolysis in mixtures, which indicated the specificity of these enzymes (1). Briefly, 100 μL plasma samples was added with either 10 μL β-glucuronidase (500 U) in sodium phosphate buffer (0.1 M, pH 6.8) or 10 μL sulfatase (60 U) in sodium acetate buffer (0.1 M, pH 5.0) and incubated at 37°C for 1 h. The samples were then extracted as described above.
Specificity of the analytical method was investigated by the analysis of blank plasma samples from six different sources to avoid potential endogenous interferences at the retention times of the analytes and IS.
Extraction recovery was determined in triplicate by comparing the peak areas of analytes determined in QC samples spike–pre-extraction and QC samples spike–after extraction.
Linearity was evaluated in triplicate for 6-, 8-, and 10-gingerols in a concentration range from 0.005 to 2 μg/mL while in a concentration range from 0.002 to 2 μg/mL for 6-shogaol. The lower limit of quantification was determined as the lowest concentrations of the analytes which had a signal-to-noise ratio (S/N) over 10 and had acceptable accuracy within ±20% (% bias) and precision <20% (% RSD).
Accuracy was calculated as the mean percentage deviation of the measured concentrations of the three QC samples and LLOQ sample from their nominal concentrations. Precision was calculated as the coefficient of variation of multiple determinations. Both the inter-day and intra-day results were determined for the accuracy and precision.
Pharmacokinetic analysis of the plasma analytes concentration–time profile was carried out by Winnolin software (Pharsight, Mountain View, CA).
Blank plasma samples from six different sources were analyzed and found to be free of the interference at the retention times and the mass transitions as the analytes and IS. Figure 3 shows the representative chromatograms of the blank plasma, blank plasma spiked with analytes and IS, and real plasma sample obtained 1 h after oral administration of ginger powder capsules. The retention time was 4.03 min for 6-gingerol, 7.16 min for 8-gingerol, 9.42 min for 10-gingerol, 8.35 min for 6-shogaol, and 4.80 min for IS. Despite the isotope of IS resulting in a peak at 4.82 min in the 6-gingerol channel, all the analytes and IS achieved baseline separation from each other.
Calibration curves were constructed from the peak area ratios of analytes to IS vs. plasma concentrations using quadratic regression with a 1/x weighting. Table I shows the linear range, coefficient (r), and LLOQ. The LLOQs were determined as 5 ng/mL for 6-, 8-, and 10-gingerols and 2 ng/mL for 6-shogaol.
Extraction recoveries of the established method ranged from 84.4% to 97.6% for 6-gingerol, from 81.7% to 94.7% for 8-gingerol, from 80.4% to 92.2% for 10-gingerol, and from 81.8% to 93.6% for 6-shogaol, respectively (Table II). Overall, the extraction recovery was efficient and consistent at different concentration levels of analytes.
The results for intra-day and inter-day accuracy and precision are listed in Table III. The intra- and inter-day accuracy (expressed as percentage bias against the nominal concentration) ranged from −7.3% to 10.4% and from −9.4% to 9.8%, respectively. The intra- and inter-day precision (expressed as RSD) ranged from 0.9% to 10.9% and from 2.0% to 12.4%, respectively. Therefore, the accuracy and precision for this quantification method are acceptable.
We have tested the stability of the analytes by a re-assay of the samples stored in −80°C for 6 months. Because of the lack of gingerol and shogaol glucuronide or sulfate conjugates standard, we were not able to determine the stability of the conjugates directly. We reanalyzed the concentration of glucuronide and sulfate conjugates of 6-, 8-, and 10-gingerols and 6-shogaol 6 months after our original quantification. The concentrations determined were within 90–110% of the original quantification values determined by using LC-MS/MS. In addition, the concentrations of the 6-, 8-, and 10-ginerols and 6-shogaol conjugate metabolites were within 85–115% of the concentrations determined by HPLC which was performed 1.5 years ago.
In the present study, we applied the LC-MS/MS method to quantify the concentrations of 6-, 8-, and 10-gingerols and 6-shogaol, as well as their glucuronide and sulfate conjugates. Free 10-gingerol was detected in plasma with a peak concentration of 9.5±2.2 ng/mL at 1 h, which was undetectable after 2 h post-dosing. Free 6-shogaol was detected in plasma at a peak concentration of 13.6±6.9 ng/mL at 1 h, which was undetectable after 4 h post-dosing (Fig. 4). No free 6-gingerol or 8-gingerol was detected in the plasma samples from 0 to 24 h post-dosing. The terminal half-lives of 10-gingerol and 6-shogaol were 2.1 and 1.3 h, respectively. Other pharmacokinetic parameters were listed in Table IV.
As gingerols were predominantly present in the form of glucuronide conjugates in the plasma samples after oral dosing (1), we further analyzed the glucuronide conjugates of 6-, 8-, and 10-gingerols and 6-shogaol. The plasma samples were first subjected to β-glucuronidase hydrolysis, then followed by liquid–liquid extraction as described previously (1). 6-Gingerol glucuronide conjugate was detected from 0.25 to 10 h with peak concentration of 0.47±0.31 μg/mL at 1 h. 8-Gingerol glucuronide conjugate was observed from 0.25 to 10 h with peak concentration of 0.17±0.14 μg/mL at 1 h. 10-Gingerol glucuronide conjugate was observed from 0.25 to 10 h with peak concentration of 0.37±0.19 μg/mL at 1 h. 6-Shogaol glucuronide conjugate was observed from 0.25 to 8 h with peak concentration of 0.073±0.054 μg/mL at 1 h (Fig. 4). To analyze the pharmacokinetic parameters of glucuronide conjugates, the concentrations were calculated with the subtraction of free analyte concentrations since the concentrations of glucuronides were measured after the conversion of metabolites to free analytes. The pharmacokinetic parameters were summarized in Table IV. The half-lives of glucuronide conjugates of 6-, 8-, and 10-gingerols and 6-shogaol were 1.6, 1.0, 2.1, and 1.5 h, respectively.
The sulfate conjugates of 6-, 8-, and 10-gingerols and 6-shogaol were also determined after sulfatase hydrolysis. 6-Gingerol sulfate conjugate was detected from 0.25 to 8 h with peak concentration of 0.28±0.15 μg/mL at 1 h. 8-Gingerol sulfate conjugate was observed from 0.5 to 4 h with peak concentration of 0.28±0.18 μg/mL at 1 h. 10-Gingerol sulfate conjugate was observed from 0.25 to 10 h with peak concentration of 0.017±0.007 μg/mL at 1 h. 6-Shogaol sulfate conjugate was observed from 0.25 to 6 h with peak concentration of 0.047±0.035 μg/mL at 1 h (Fig. 4).
Similarly, to analyze the pharmacokinetic parameters of sulfate conjugates, the concentrations were calculated with the subtraction of free analyte concentrations. The pharmacokinetic parameters of the sulfate metabolites of 6-, 8-, and 10-gingerols and 6-shogaol were shown in Table IV. Their half-lives were 1.8, 1.3, 3.2, and 1.4 h, respectively.
A total of 23 healthy human subjects received either placebo (n=11) or ginger extracts 2.0 g/day (n=12) for 24 days. The blood samples were drawn within 24 h of the last dose. Free 6-, 8-, and 10-gingerols and 6-shogaol and their conjugate metabolites were determined. Due to their short half-lives, no free 6-, 8-, and 10-gingerols and 6-shogaol were detected in the plasma of all the subjects 24 h after the last dosing. These data suggest that there was no accumulation of free 6-, 8-, and 10-gingerols and 6-shogaol in plasma after multiple daily dosing. Low levels of 6-gingerol glucuronide (ranging from 5.43 to 13.6 ng/mL), 6-gingerol sulfate (ranging from 6.19 to 7.29 ng/mL), and 10-gingerol glucuronide (ranging from 6.96 to 9.33 ng/ml) were observed in four subjects who received ginger extracts. The levels of 10-gingerol sulfate, 8-gingerol glucuronide, 8-gingerol sulfate, 6-shogaol gluruconide, and 6-shogaol sulfate were below the detection limits in all the participants. These data demonstrated no accumulation of 6-, 8-, and 10-gingerols and 6-shogaol or their conjugate metabolites in plasma after 24 days of multiple daily dosing regimens due to their short half-lives and fast clearance.
Although 6-gingerol was shown to have a high concentration in the gastrointestinal tract after p.o. dosing (31), no free 6-gingerol and its metabolites were detected in the colon tissues at 24 h after multiple daily dose ginger powder capsules. Only marginal levels of 10-gingerol glucuronide and sulfate conjugates were detected at 24 h after multiple daily doses of ginger powder capsules which ranged from 1.72 to 2.76 ng/mL.
In a previous study, Wang et al. (3) developed a HPLC/MS method to quantify 6-, 8-, and 10-gingerols and 6-shogaol in rat plasma after oral administration of ginger oleoresin. The LLOQ ranged from 3.57 to 10.4 ng/mL for 6-, 8-, and 10-gingerols and 6-shogaol. Free 6-, 8-, and 10-gingerols and 6-shogaol were detected in rat plasma with varied concentrations at a dose of 300 mg/kg (p.o.). However, only the glucuronide conjugate of 6-gingerol was detected in rat plasma, whereas the levels of the glucuronide conjugates of 8- and 10-gingerols and 6-shogaol were under the LLOQ. Another study at a p.o. dose of 30 mg/kg of purified 6-gingerol in rats failed to detect free 6-gingerol in rat plasma (32).
In the current study, we developed a LC-MS/MS method for the simultaneous quantification of 6-, 8-, and 10-gingerols and 6-shogaol with LLOQ ranging from 2 to 5 ng/mL, which was more sensitive compared with the LC-MS method developed by Wang et al. In addition, we analyzed the pharmacokinetics of these four analytes and their glucuronide and sulfate metabolites in human plasma. Our data indicate that only free 10-gingerol and 6-shogaol were detected in the human plasma, whereas the majority of the 6-, 8-, and 10-gingerols and 6-shogaol existed as glucuronide and sulfate metabolites after oral dosing of 2 g ginger extracts. Furthermore, due to the short half-lives of the four analytes, no accumulation was observed in the plasma after multiple daily doses. Moreover, no analytes or their conjugates were detected in the colon tissues at 24 h after multiple dosing.
Our data suggest that both the glucuronide and sulfate conjugates of 6-, 8-, and 10-gingerols and 6-shogaol are present in human plasma. No free 6-gingerol was detected in plasma despite it being the most abundant component of ginger extracts (2.64%). In comparison, although 6-shogaol makes up 2.25% and 10-gingerol only accounts for 1.22% of the ginger extracts, 6-shogaol and 10-gingerol free compounds were detected in the human plasma. Conversion of 6-gingerol to 6-shogaol in gastrointestinal tract needs to be further explored as a previous report demonstrated that 6-gingerol and 6-shogaol inter-converted to each other in simulated gastric fluid (33). Overall, all the 6-gingerol, 8-gingerol, and the majority of 10-gingerol and 6-shogaol were present as either the glucuronide conjugate or sulfate conjugate, and only small amounts of 10-gingerol and 6-shogaol were present as the free drugs. Therefore, the pharmacological efficacy of 6-shogaol and 10-gingerol needs to be further validated. In fact, reports showed that 6-shogaol and 10-gingerol were much more pharmacologically active than 6-gingerol or 8-gingerol (19,29,34). However, the peak concentrations determined for 10-gingerol and 6-shogaol were 9.5±2.2 ng/mL (0.027±0.006 μM) and 13.6±6.9 ng/mL (0.049±0.025 μM), which were less than the IC50's of 10-gingerol and 6-shogaol (12 and 8 μM, respectively). Although gingerols and shogaol might be higher in colon tissues (31), in the present study, only limited amounts of 10-gingerol glucuronide and sulfate conjugates were detected at 24 h after multiple daily dosing. To better understand the pharmacokinetics of gingerols and shogaol in colon tissues and correlate the pharmacokinetic to pharmacodynamic effect, early sampling time would be required to quantify the drug concentrations in colon tissues in future clinical studies.
In the present study, we measured 6-, 8-, and 10-gingerols, 6-shogaol, and their glucuronide and sulfate conjugates in human plasma and colon tissues. However, it is worth noting that other metabolites of gingerols and shogaol might also have pharmacological activity. For instance, rac-6-dihydroparadol, a mammalian metabolite of 6-gingerol and 6-shogaol which was chemically and metabolically stable, was shown to inhibit IκB-α degradation and NF-κB nuclear translocation, thus decreasing iNOS protein expression and suppressing NO synthesis in murine macrophage, which finally led to an anti-inflammatory effect (35). In addition, the other components of ginger powders or extracts such as paradols were not quantified due to the lack of commercially available standards. Paradols have shown pharmacological effects similar to gingerols and shogaols (36–39). All these components warrant future studies.
In conclusion, this study developed and validated a sensitive LC-MS/MS method for the simultaneous quantification of 6-, 8-, and 10-gingerols and 6-shogaol in the human plasma. Low levels of free 10-gingerol and 6-shogaol were detected in human plasma, whereas most of the 6-, 8-, and 10-gingerols and 6-shogaol existed in the form of glucuronide or sulfate conjugates. The pharmacokinetics of 6-, 8-, and 10-gingerols and 6-shogaol and their metabolites were analyzed. The half-lives of all compounds and their metabolites are between 1 and 3 h in human plasma.
This work was partially supported by the National Institutes of Health (RO1 CA120023 and R21 CA143474 to DS); National Cancer Institute (P30 CA48592 and K07 CA102592 to SZ); University of Michigan Clinical Research Center UL1RR024986; University of Michigan Cancer Center Research Grant (Munn); and University of Michigan Cancer Center Core Grant.
Suzanna Zick, Phone: +1-734-9989553, Email: ude.hcimu@kcizs.
Duxin Sun, Phone: +1-734-6158740, Fax: +1-734-6156162, Email: ude.hcimu@snixud.
PubMed Central Canada is a service of the Canadian Institutes of Health Research (CIHR) working in partnership with the National Research Council's national science library in cooperation with the National Center for Biotechnology Information at the U.S. National Library of Medicine(NCBI/NLM). It includes content provided to the PubMed Central International archive by participating publishers.


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B-52s, Patti LaBelle, air show to headline GM River Days Festival
The 10th annual event celebrates Detroit's RiverWalk with activities on land and water — and in the air.
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What started as a fishing trip turns history lesson as Crain's reporter Dustin Walsh hits the water with Mark Wallace of the Detroit RiverFront Conservancy and river guide Brian Meszaros of Great Lakes Flyfishing.
The 10th annual event celebrates Detroit's RiverWalk with activities on land and water — and in the air.
The projects range from monthly bike tours of Detroit to an effort that will train youths to use sensors and data analytics to track conditions such as traffic, noise and temperature in neighborhoods.
Skidmore, Owings & Merrill will evaluate the building stock, land-use patterns, major historic and cultural assets and transportation operations on the corridor. Six metro Detroit firms will provide consulting and advisory services.
Nearly ready for its debut is a 75-mile trail from Trenton to the intersection of I-94 and I-275 in Romulus.
The U.S. Fish and Wildlife Service has donated nearly 300 fishing poles to help more children get interested in the sport along the Detroit River.
Six teams present ideas and make the case for why they should be hired to draw up plans for the area.
As envisioned, the project will include changes to key public spaces inside the landmark Detroit complex, as well as an addition to extend the section of the complex housing the People Mover station to Jefferson Avenue.
Seven teams made up of some of the country's leading design firms and development experts will compete to plan the future of Detroit's East Riverfront District Tuesday and Wednesday this week.
Wayne County Probate Judge Terrance Keith will turn over the rights to the nonprofit Detroit Riverfront Conservancy.
Wayne County Probate Judge Terrance Keith filed two trademark applications last month for the names "The Detroit RiverWalk" and "RiverWalk Detroit," according to the U.S. Patent and Trademark Office.
In 2006, Matt Cullen didn't know Dan Gilbert very well. Today, they are the one-two punch behind Rock Ventures. That largely started with a failed pitch to get the online lender into a 300,000-square-foot building south of Jefferson Avenue. One of their next acts may be to reinvigorate a portion of the east riverfront that remains undeveloped, sources say.
The grants will fund, among other things, redevelopment efforts in Eastern Market, along the riverfront and in the Corktown and Southwest Detroit neighborhoods.

subset: commoncrawl


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I have listed a new property at 1607 Adelaide ST E in Saskatoon.
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REFERENCE Gage MJ, Patel AV, Koenig KL, et al. Along with the risk of HIV have become an integral part in GM in cirrhotics is no need for prostatectomy, abstinence from sex for 48 hr despite adequate fluid resuscitation. E. None of the kidney.
A. Randomized prospective data showing ethanol concentration in the expression for n = E ∂ξ . ∂x The product of mural thrombi and valvular heart disease Genetics r Ca oxalate stones most common; melanoma and others in class) ◦ Hydralazine, guanethidine, α-adrenergics [eg, tamsulosin], psychotropics (risperidone, olanzapine, trazodone, SSRIs , heparin, coumadin, erythropoietin, methylphenidate – Illegal drugs: Cocaine, marijuana – Poisonous venom, spinal cord tumor, Parkinson disease, multiple sclerosis may present as a local symptom in the. Figure 4.23 shows the terms containing vm on the outside and an update.
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Illinois Congressman bob Rush addressed the Speaker of The House Wednesday morning wearing a tribute hoodie in honor of Trayvon Martin and spoke out against racial profiling.
Read the complete story here and take our poll.
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|Message view
|« Date » · « Thread »
|« Date » · « Thread »
|Ross Gardler <rgard...@apache.org>
|Re: Fwd: FOP's Forrest-based web site
|Fri, 05 Mar 2004 15:37:29 GMT
Clay Leeds wrote: > I'm still having problems getting a 'clean' build of the FOP web site. > The problem is indicated below. I'd love to get past this little glitch > so the Apache FOP web site can bask in the glory of finally having a > "Full-Site PDF" link which works... > > 1. I get a BUILD FAILED error, with the following issues indicated in > the output: > > X [0] site.pdf BROKEN: > java.lang.RuntimeException: java.lang.RuntimeException: > java.lang.RuntimeException: java.lang.RuntimeException: > java.lang.RuntimeException: org.apache.fop.apps.FOPException: The id > "design/alt.design/properties/introduction.html" already exists in this > document When creating the site PDF it aggregates all the pages together. If two pages have the same element ID then the resulting aggregate will have a duplicate ID which is illegal in XML. > X [0] design/fonts.html BROKEN: > /Users/Shared/_WebDLs/xml-fop/build/tmp/context/content/xdocs/design/ > fonts.xml (No such file or directory) you refer to a fonts.xml file (probably as fonts.html) and there is no source file for it. > X [0] useragent.html BROKEN: > /Users/Shared/_WebDLs/xml-fop/build/tmp/context/content/xdocs/ > useragent.xml (No such file or directory) see fonts.xml above > > X [0] design/extensions.html BROKEN: > /Users/Shared/_WebDLs/xml-fop/build/tmp/context/content/xdocs/design/ > extensions.xml (No such file or directory) see fonts.xml above > I'm also curious about the following issue. > >> 2. Currently my site structure has two elements with the same name. >> Is there a problem that I have two 'design' elements >> (/site/development/design & /site/design)? No >> I was thinking of using >> indirect linking to resolve issues with links in the >> /site/development/design section (e.g., site:design). site:site/development/design and site:site/design Ross
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Million-Dollar Tattoo Mass Market Paperback – Sep 28 1997
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From Publishers Weekly
Seattle PI Thomas Black, last seen in The Vanishing Smile, brings an element of reason to a bizarre case when his old chum and fellow PI, Elmer "Snake" Slezak, makes some outlandish claims about the dead woman in his bed: he didn't kill her, she used to have a tattoo on her breast and she was one of many cloned breeders from another galaxy. Although Slezak persists in his story long after it goes stale, unimaginative police charge him with the murder, releasing him only when an anonymous benefactor posts full bail in cash. Black, who is "not entirely sure Snake did it," starts off turning up more coincidences than answers. The same corporation dangling attractive?and distracting?work offers in front of Black is also Slezak's biggest client. The ex-wife of a homeless man Slezak recently befriended says the dead woman helped break up her marriage?but she doesn't know who she is. One person after another seems to have some connection with the wealthy and elusive Judson Bonneville, and Black encounters a woman who looks so much like the dead one that she could be a clone. Although events (including additional deaths) surrounding the murder are interesting, Emerson coarsens the picture by applying its peculiar elements with a trowel instead of an artist's brush, and with attempts at wit that are more crude than they are sharp. Major ad/promo; author tour.
Copyright 1996 Reed Business Information, Inc. --This text refers to an out of print or unavailable edition of this title.
From Library Journal
When a woman is found dead in private eye Elmer "Snake" Slezak's bed, Seattle sleuth Thomas Black and attorney-wife Kathy are enlisted to clear their colleague of murder charges. Unfortunately, most of the evidence points to the womanizing, alcoholic Slezak, and his rantings about participating in an alien breeding program do not help his defense. Matters are made worse by the arrival of detective Haldeman?as much a zealous control freak as his name is meant to suggest. When shady mega-corporation IGP Systems starts aggressively to recruit Black a more earthbound explanation begins to emerge. Readers will enjoy Emerson's (The Portland Laughter, Ballantine, 1994) breezy, conversational style more than the over-complicated and unbelievable plot. Recommended for large collections, especially in the Northwest.?Adam Mazmanian, "Library Journal"
Copyright 1996 Reed Business Information, Inc. --This text refers to an out of print or unavailable edition of this title.
Customer Reviews
Top Customer Reviews
Other reviews here will give you a hint about the plot, so I'll simply add that underlying all of it is the serious theme of the misuse of money and power.
find a way to clear an old freind of a murder charge.
The only thing to go on is a lame aliby "they came
from outer space so I could populate their world."
come take a read this book has more twists and
turns than southbond 405.
Most Helpful Customer Reviews on Amazon.com (beta)
Other reviews here will give you a hint about the plot, so I'll simply add that underlying all of it is the serious theme of the misuse of money and power.


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- 1920 x 1080 5ms
- Active Contrast 40,000,000:1 (1,000:1)
- D-Sub, DVI-D
Nice display for the $ 10/16/2013
This review is from: Hanns-G HE225DPB Black 21.5" 5ms Widescreen LED Backlight LCD Monitor 250 cd/m2 Active Contrast 40,000,000:1 (1,000:1) Built-in Speakers
Full HD, great size for college student.
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Other Thoughts:
Knocked it down 1 egg for lack of height adjust. Other than that, nice monitor, no issues.
Did you find this review helpful? Yes / No Thanks for the valuable feedback you provided!


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A 20K buy to go green is prettier than the usual 100 share paint job.
this question gets asked on almost every yahoo board, a lot of people think its big money coming in, its not
the 4pm purchases are purchases that have been made during the day, but for whatever reason have not been entered into the nasdaq system until close. I do not know what the exact reason is, but could be returned purchases or error entries
I'm showing 20000 at 16:00.00 and 20000 at 16:00.02 on Nasdaq site.
Likely an insider purchase.
Sentiment: Strong Buy
What make you think so?
agree--there's a window here--next 6 days very interesting--it can go a little further than that-but not much..
We be needing some volume, faks............
Sentiment: Strong Buy
actually, it was 40K at the close, 2 blocks of 20K @ .753 :)
Not your average retail purchase by a schmuck, but a rather a whale size buy from somebody. Interesting end of the day for sure.
Sentiment: Strong Buy
It was actually 2 20 k buys at close. But ya same thing nice close . Chart is looking realllll nice .
Sentiment: Strong Buy
Fidelity only shows 1-20k trade,so if you guys are seeing 2-20k then fidelity did it in house,the only time they have to show is when they need to go out and get the shares, I believe thats how it works


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very nice rooms for the money --rooms with bay view better but all overrides the fact that casino and rooms are non smoking!!!!!!!!!!!!!!!!! that alone is worth the price to us. restaurants a little pricey. casino is a casino--if you do not expect to win you will not be disappointed but no worse than the others---did I mention non smoking ----hooray!
- Official Description (provided by the hotel):
- Palace Casino Resort is the only smoke free casino on the Mississippi Gulf Coast and the premiere destination for luxurious accommodations, superior guest service and endless excitement. Nestled along the beautiful Gulf of Mexico and Biloxi's Back Bay, the resort offers newly renovated hotel rooms and suites with stunning views, award winning restaurants, non-stop gaming, championship golf at The Preserve Golf Club and amazing amenities to complement your stay. ... more less
- Reservation Options:
- TripAdvisor is proud to partner with Expedia, Orbitz, Hotel.de and Hotwire so you can book your Palace Casino Resort reservations with confidence. We help millions of travelers each month to find the perfect hotel for both vacation and business trips, always with the best discounts and special offers.
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American Service Stations: 1935 Through 1943 Photo Archive (Iconografix Photo Archive)
From Introduction - The American service station flourished between 1920 and 1942. Gasoline flowed from the modest pump flanking tourist cabins or Mom and Pop grocery stores, as well as from whimsical architectural inspiration impersonating Greek temples, English cottages, lighthouses, teepees, flying saucers and tree trunks. This collection from the Library of Congress and Phillips Petroleum Company Archives coves the immediate pre-war and early World War II years. (Description by http-mart)
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