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HERBAL MEDICINE |
From IMFORM GmbH International Clinical Research, Darmstadt, Germany (Dr Frank); Institute of Nutrition, Justus-Liebig-University, Giessen, Germany (M Janßen, Dr Bitsch); Institute of Nutrition, Friedrich-Schiller-University, Jena, Germany (Dr Netzel, G. Straß); and Plantextrakt GmbH & Co KG, Vestenbergsgreuth, Germany (Dr Kler, E. Kriesl).
Address for reprints: Dr Thomas Frank, IMFORM GmbH International Clinical Research, Birkenweg 14, D-64295 Darmstadt, Germany.
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ABSTRACT |
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 TOP ABSTRACT METHODSRESULTSDISCUSSIONCONCLUSIONACKNOWLEDGEMENTSREFERENCES |
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Key Words: Hibiscus sabdariffa L. extract • anthocyanins • anthocyanidin-3-glycosides • pharmacokinetics • herbal medicine
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Consumption of anthocyanins, present in fruit and vegetable products, has been shown to reduce the risk of coronary heart disease and to prevent some chronic diseases.4,5 The positive physiological effects of these plant pigments could be related to their potent antioxidant activity demonstrated in various in vitro and in vivo studies.6-11 H. sabdariffa L. has gained an important position in the soft drink and medicinal herb market, although its biological and pharmacological effects are still poorly defined. Recent in vivo investigation in rats showed that oral pretreatment of HA for 5 days before a single dose of tert-butyl hydroperoxide significantly lowered the serum levels of hepatic enzyme markers and reduced oxidative liver damage.12 Chronic administration of an aqueous H. sabdariffa extract (HSE) exhibited antihypertensive and cardioprotective effects in hypertensive rats.13
In contrast to new drugs that have to be subjected to an extensive clinical development program before approval, the food law does not provide a systematic procedure by which the pharmacokinetics are to be evaluated for foodstuffs or ingredients of foodstuffs with assumed therapeutic potential or protective effects in man. HSE contains basically monomeric and some copigmented and polymeric anthocyanins. Their concentrations vary according to the processing method and storage time. All of them are very effective antioxidants, radical scavengers, and ferric-reducing compounds14—the precondition for their biological activity and potential benefit for human health. To understand if they are active in the human body, a thorough knowledge of their bioavailability is thus essential. It is therefore crucial that we understand the pharmacokinetics of dietary anthocyanins and the differences that may occur if we are to sort out the potential health benefits of both unchanged anthocyanins and anthocyanin metabolites to the human body. In this study, we compare the pharmacokinetic parameters of monomeric anthocyanidin glycosides from a single oral dose of dietary anthocyanins following consumption of HSE. The pharmacokinetic parameters may be useful for selecting the dose and dose frequency for intervention studies with HSE. They can also serve as a basis for designing in vitro experiments on the mechanisms of action of anthocyanins at the cellular and molecular levels.
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METHODS |
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TOPABSTRACTMETHODSRESULTSDISCUSSIONCONCLUSIONACKNOWLEDGEMENTSREFERENCES |
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Before entering the study, subjects underwent a screening evaluation, including medical history and physical examination. Participants adhered to their usual diet but had to abstain from food and beverages rich in anthocyanins or polyphenols from 24 hours prior to treatment. They were instructed to refrain from alcohol and medications, including over-the-counter drugs, throughout the study.
The trial was an open-label, single-center study performed under controlled conditions at the human nutrition unit of Giessen University's Institute of Nutrition. Appropriate standards for human experimentation have been followed. Each subject consumed 10 g of HSE (powder) that was diluted with 150 mL tap water. The ingested total anthocyanin dose was 147.4 mg (calculated as cyanidin equivalents). At 0800 hours after an overnight fasting, volunteers took the diluted extract together with white rolls (Table I). During the experimental period, only the consumption of water was allowed.
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For the determination of the pharmacokinetic profile of anthocyanins in plasma, venous blood samples were drawn predose as well as 0.5, 1, 1.5, 2, and 3 hours after administration of the dose. Each blood sample (9 mL) was collected in an EDTA-coated tube. The blood samples were centrifuged within 10 minutes after collection, and the resulting plasma (2 mL) was mixed with 0.44 M trifluoroacetic acid (TFA, 0.4 mL) to avoid deterioration of anthocyanins. The stabilized plasma samples were transferred into storage tubes immediately and stored frozen at –80°C until analyzed.
Urine samples were collected predose and quantitatively in 1-hour intervals up to 7 hours after dosing (0-1, 1-2, 2-3, 3-4, 4-5, 5-6, and 6-7 hours). The total volume of urine was measured for each collection period in a measuring cylinder to the nearest 10 mL, and aliquots (7 mL) were acidified with formic acid (2 mL) and stored frozen at –80°C until assayed.
The stabilized plasma and urine samples were diluted with a high-performance liquid chromatography (HPLC) mobile phase (pH 1.6) before HPLC analysis. At a pH below 2, anthocyanins exist primarily in the form of the flavylium cation, which is the most stable form, and the quinoidal, chromenol, and chalcone forms of anthocyanins are converted to this form at acidic pH (0-2).
Bioanalytical Methods
Unless otherwise stated, all chemicals were purchased from Merck (Darmstadt, Germany). Delphinidin-3-glucoside was purchased from Polyphenols AS (Sandnes, Norway), cyanidin-3-glucoside was provided by Roth (Karlsruhe, Germany), and cyanidin-3-sambubioside and delphinidin-3-sambubioside were provided by the Institute of Food Chemistry of the Technical University at Braunschweig (Braunschweig, Germany). The HSE was obtained from Plantextrakt (Vestenbergsgreuth, Germany).
The concentrations of the 3-O-glycosides of cyanidin and delphinidin in urine and plasma were determined by a validated HPLC method with UV-Vis (ultraviolet–visible) and photodiode array detection described elsewhere.15,16 Briefly, the validation data of the methodology for workup and analyses of anthocyanins in urine and plasma were as follows: recoveries were higher than 79% in urine and 80% in plasma. The intra- and interday variations were below 10.5% in both sample types, and the limit of quantification (S/N 
10) was between 1.3 and 6.0 ng/mL in both matrices. Calibration curves (mean correlation coefficient of 0.998) were prepared by spiking blank urine and plasma with known concentrations of standard solutions prior to the preparation procedures.
Pharmacokinetic Evaluation
Concentrations of the monomeric anthocyanins (calculated as cyanidin equivalents) and their sum (referred to as total anthocyanins) in urine and plasma were evaluated. Noncompartmental pharmacokinetic evaluation was performed according to standard methods17 using the WinNonlin Professional software (version 4.1, Pharsight Co, Mountain View, Calif). All calculations were based on the assayed concentrations and the scheduled times. The primary target pharmacokinetic parameters were derived from urinary concentrations. The use of noncompartmental analysis for urine data was based on the following input data: starting and ending time of each urine collection interval, urine concentrations, and urine volumes. From these data, WinNonlin computed the midpoint of each collection interval and the excretion rate for each interval (R) to be used in the analysis according to equation (1):
 | (1) |
t denotes the length of the sampling interval. The following pharmacokinetic parameters were subsequently derived from urinary excretion rates: the maximal observed excretion rate (Rmax), the midpoint of the collection interval associated with the maximal observed excretion rate (tmax,R), and the area under the urinary excretion rate curve from time 0 to the last measured rate (AURC0-6.5).
AURC0-6.5 was calculated according to the linear trapezoidal rule. The terminal rate constant was calculated by log-linear regression of the terminal segment of the excretion rate versus time curve. The optimal regression fit was determined by WinNonlin using at least the 3 last quantifiable concentrations as the period of the highest possible coefficient of correlation. The negative value of the slope of the fitted log-linear regression line is the terminal rate constant (
z), and ln (2) divided by z is the terminal half-life (t1/2). Using z and the excretion rate at the midpoint of the last collection interval (R6.5), the expected total amount of anthocyanins excreted in urine (Ae
) was extrapolated by equation (2).
 | (2) |
only considered those results for which AURC%Extrap accounted for less than 20% of the total area. Besides, the observed total amount recovered in urine from time 0 up to 7 hours (Ae0-7) was determined by multiplying the concentration of the respective anthocyanin in urine by the volume of the urine sample in each collection interval and then calculating the sum of all intervals after dosing. The relative amount excreted into urine within 7 hours (fe/f), expressed as a percentage of dose, was calculated by dividing Ae0-7 by the respective dose of anthocyanin administered. Values below the lower limit of quantification (LLOQ) were set to 0.
The following secondary pharmacokinetic parameters were evaluated in plasma: maximal concentration in plasma (Cmax), time to reach maximal concentration (tmax), and area under the concentration-time curve from time 0 up to the time of the last measured concentration (AUC0-3). AUC0-3 was calculated according to the linear trapezoidal rule. For comparison purposes, AUC0-3 and Cmax were normalized by dividing the values by the administered dose.
Statistical Evaluation
A comprehensive data summary was performed by means of descriptive statistics for all continuous target parameters (number of observations, arithmetic mean, standard deviation [SD], median, minimum, maximum, geometric mean, and geometric coefficient of variation [CV%]).
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RESULTS |
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TOPABSTRACTMETHODSRESULTSDISCUSSIONCONCLUSIONACKNOWLEDGEMENTSREFERENCES |
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The results of the pharmacokinetic analysis of the 6 subjects enrolled in the trial are summarized in Tables II and III. The mean excretion of anthocyanins in urine during each collection interval is presented as excretion rates in Figure 2. After reaching the peak rate, a monoexponential decay of anthocyanin excretion seems probable.
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After ingestion of HSE, maximum excretion rates (Rmax) of 2.82 and 4.89 µg/h were determined for cyanidin-3-sambubioside and delphinidin-3-sambubioside, respectively. They were reached quickly, with tmax,R values of 1.5 and 2.0 hours (median) after intake, respectively. Interindividual variability of Rmax, as characterized by the geometric coefficient of variation, was large, with values above 60% (Table II). Maximum excretion rates were not determined for cyanidin-3-glucoside and delphinidin-3-glucoside as urinary concentrations were below the LLOQ. The estimate of the maximum excretion rate of total anthocyanins was determined to be 7.51 µg/h, occurring 1.5 hours (median) after consumption of HSE. Subjects M3, W2, and W3 exhibited Rmax of total anthocyanins that were more than twice the value of subjects M1 and M2 (Figure 3).
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The relative amount excreted of cyanidin-3-sambubioside, delphinidin-3-sambubioside, and total anthocyanins during 7 hours was very low and did not differ among the measured compounds, with values of 0.016%, 0.021%, and 0.018%, respectively (Table II). Although the urinary excretion of total anthocyanins was generally very low, their interindividual variability proved to be large, with geometric CVs around 60%. Subject W1 exhibited with 11 µg, the lowest excretion (0.007% of the administered dose), whereas subjects M3, W2, and W3 showed the highest values of 53, 36, and 33 µg (corresponding to 0.036%, 0.025%, and 0.022% of the administered dose), respectively.
The terminal half-lives (t1/2) for cyanidin-3-sambubioside, delphinidin-3-sambubioside, and total anthocyanins were short, with values of 2.18, 3.34, and 2.63 hours, respectively (Table II). Interindividual variability in t1/2 was largest for cyanidin-3-sambubioside (geometric CV of 78%); the estimates of t1/2 were within a range of 1.15 hours (subject W2) to 7.5 hours (subject M3). Variability in t1/2 was lowest for total anthocyanins (geometric CV of 31%), with values ranging from 1.7 hours (subject W2) to 3.95 hours (subject M3).
Figure 4 illustrates the mean concentration versus time course of all anthocyanins assayed in plasma during the first 3 hours following administration of HSE. Peak plasma concentrations occurred nearly at the same time as urinary excretion rates did (Figures 3 and 5). The renal excretion rates and plasma concentrations decayed almost in parallel. Compared to the excretion rates, the concentration versus time courses in plasma exhibited a smaller interindividual variability.
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The oral absorption of anthocyanins from HSE was fast, without any lag time. Estimates of maximum plasma concentration were low, with 2.2, 1.3, and 3.4 ng/mL for cyanidin-3-sambubioside, delphinidin-3-sambubioside, and total anthocyanins, respectively (Table III). Peak plasma times, with a median value of 1.5 hours after intake, did not differ obviously among the assayed anthocyanins. Peak plasma concentrations were not determined for cyanidin-3-glucoside and delphinidin-3-glucoside because concentrations were below the LLOQ.
The dose-normalized AUC0-3 of cyanidin-3-sambubioside was 2.4 times higher as compared with delphinidin-3-sambubioside (0.076 vs 0.032 ng·h/mL/mg) (Table III). In general, the interindividual variability of plasma pharmacokinetic parameters was moderate and lower as compared with the urinary pharmacokinetic parameters.
Interestingly, neither glucuronides nor sulfates or methylated metabolites of the administered HSE anthocyanins were detected in the plasma or urine samples.
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DISCUSSION |
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TOPABSTRACTMETHODSRESULTSDISCUSSIONCONCLUSIONACKNOWLEDGEMENTSREFERENCES |
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The results demonstrate that anthocyanins from HSE that possess high antioxidant activity are incorporated and excreted in urine in their intact glycosidic forms. The cumulative urinary excretion of total anthocyanins after consumption of HSE was low (0.018% of the administered dose). This finding is in line with the results found in our previous investigations on dietary anthocyanin pharmacokinetics. After consumption of a single dose of red grape juice or red wine, urinary excretion of total dietary anthocyanins during 7 hours was 0.23% and 0.18% of the administered dose, respectively.15 Only 0.04% of the administered dose of total anthocyanins was excreted in unchanged form within 7 hours after the ingestion of blackcurrant juice.16 Within 32 hours, Rechner et al18 found that 0.007% to 0.133% of the dose was excreted, whereas Lapidot et al19 found a relatively high urinary recovery within 12 hours, ranging between 1.5% and 5.1% after administration of red wine containing 218 mg of anthocyanins. These high urinary recoveries of red wine anthocyanins, however, were based on the detection of both unchanged anthocyanins and "anthocyanin-like" compounds.
Considerable evidence is now available supporting the hypothesis that deglycosylation is a rate-limiting step for absorption of dietary flavonoid glycosides in the small intestine. Nemeth et al20 demonstrated that 2 human ß-glucosidases—that is, lactase-phlorizin hydrolase (LPH) and the cytosolic ß-glucosidase (CBG)—present in the epithelial cells of the small intestine function to deglycosylate flavonoid glycosides during passage across the gut wall. However, mainly quercetin glucosides (onion) and a small portion of quercetin monoglycosides (apples) are substrates for these ß-glucosidases, but not anthocyanins.20 This could explain the low bioavailability of anthocyanins, which were not hydrolyzed to their aglycones in the intestine and are only absorbed as intact glycosides in small amounts. The tested HSE contained amounts of 3-O-glucosides of cyanidin and delphinidin that were too low to result in quantifiable plasma or urine concentrations. Urinary excretion and the rise of plasma concentrations of all assayed intact glycosides started quickly, which reflected rapid absorption of glycosides that would take place mainly in the small intestine. Whether the stomach could account for the rapid absorption of anthocyanins from food, as postulated by Passamonti et al,21 needs further clinical investigation.
The clinical relevance of the observed differences in renal excretion is questionable as the absolute amount excreted is negligible. Moreover, the observed differences in the small amounts excreted may result in large percentage differences and hence give rise to large interindividual variation in estimates of parameters. A combination of low absorption, subjection to rapid metabolism (eg, in vivo methylation of cyanidin to peonidin), glucuronide conjugate formation, and degradation of anthocyanins (eg, to hydroxybenzoic acids) occurs after people consume anthocyanins as well as other flavonoids.22-28 Actual findings indicate that most of the ingested polyphenols from flavonoid-rich beverages are subjected to metabolism in the colon.18
We focused on the urinary excretion of monomeric anthocyanins. Because one cannot entirely appreciate the total amount of anthocyanins absorbed from urinary recovery alone, it must be taken into account that the cumulative amount of excretion of absorbed anthocyanins might not have been properly estimated. Biliary secretion might be responsible for at least some of the elimination of the components.
The half-life estimate of total anthocyanins derived from urinary excretion in our study (2.6 hours, Table III) is only slightly higher than the 2.2 hours reported by Cao et al.23 The half-life of cyanidin-3-sambubioside was 2.2 hours in the present study and 2.8 hours in Cao et al.23 Basically, it must be taken into account that the investigational time range was only 7 hours in the present trial but up to 24 hours after intake in the study of Cao et al,23 which thus provided more realistic estimates of terminal half-life because concentrations were followed for a longer period of time. Against this background, the good comparability of the robust t1/2 parameter between studies indicates that elimination exhibits monoexponential characteristics over time.
The dose-normalized AUC and Cmax estimates determined in the present study are approximately 10 times lower than after ingestion of red grape juice or red wine.15 Recent findings suggest that the sugar content of the beverages may influence dietary bioavailability of anthocyanins because the glucose content in the intestinal lumen after ingestion of flavonoid-containing food might affect flavonoid uptake. Bub et al29 concluded that there was a delaying effect of the sugar present in red grape juice, which could result from a competitive action of glucose and anthocyanins on the sodium-dependent glucose transporter 1 (SGLT1). The opposite was observed in our previous study.15 Up to now, there has been no evidence that sugar inhibits anthocyanin absorption by SGLT1. On the contrary, there is a rapid enhancement of brush-border SGLT1 protein after exposure of the mucosa to glucose. This means that both substances can be absorbed without any interference.30 Because quercetin glucosides are capable of interacting with the sodium-dependent glucose transport receptors in the mucosal epithelium, demonstration of the presence of anthocyanins in their unchanged glycosylated forms that share a similar basic flavonoid structure might indicate the involvement of the glucose transport receptors in the absorption of these compounds in vivo.23
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CONCLUSION |
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TOPABSTRACTMETHODSRESULTSDISCUSSIONCONCLUSIONACKNOWLEDGEMENTSREFERENCES |
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In this study, our analytical procedure was directed to detect the unchanged monomeric anthocyanins in plasma and urine, and the resulting pharmacokinetic parameters indicate a low oral bioavailability of these anthocyanidin glycosides from HSE, although oral bioavailability was not explicitly examined. Studies are under way tracing both the intact glycosides and their in vivo metabolites or conjugates to evaluate the impact of anthocyanins on health-protecting properties of flavonoid- and anthocyanin-rich foods. Besides anthocyanins, H. sabdariffa L. contains other components with remarkable antioxidative and antiatherosclerotic properties (eg, protocatechuic acid). Possibly the whole complex of monomeric, polymeric, and copigmented anthocyanins and other polyphenols is responsible for the well-known biological and pharmacological properties of H. sabdariffa L., which are still poorly defined.
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ACKNOWLEDGEMENTS |
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TOPABSTRACTMETHODSRESULTSDISCUSSIONCONCLUSIONACKNOWLEDGEMENTSREFERENCES |
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FOOTNOTES |
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Submitted for publication May 10, 2004; Revised version accepted August 27, 2004.
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REFERENCES |
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TOPABSTRACTMETHODSRESULTSDISCUSSIONCONCLUSIONACKNOWLEDGEMENTSREFERENCES |
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