Glucofrangulin: A Comprehensive Reference Article
1. Identity and Chemical Characterization
1.1 Names and Classification
Glucofrangulin is the collective name for two closely related anthraquinone diglycosides — glucofrangulin A and glucofrangulin B — derived from the bark of members of the Frangula and Rhamnus plant genera. The constituents with known therapeutic activity of frangula bark include the diglycosides glucofrangulin A (emodin-6-O-α-L-rhamnosyl-8-O-β-D-glucoside) and glucofrangulin B (emodin-6-O-β-D-apiosyl-8-O-β-D-glucoside), as well as the monoglycosides frangulins A, B, and C.
The core structure of both isomers is an emodin anthraquinone aglycone linked to two sugar units. The difference between glucofrangulin A and B lies in the identity of one of these sugar moieties. Glucofrangulin is described pharmacognostically as frangula emodin glucorhamnoside. Hydrolysis of glucofrangulin yields frangulin and glucose, while hydrolysis of frangulin gives frangula emodin and rhamnose.
The molecular formula for glucofrangulin A is C27H30O14, with a molecular weight of 578.52 g/mol. Its percent composition is C 56.06%, H 5.23%, O 38.72%, with the Standard InChIKey GPSQZOFVCVOOIE-QWVHOXPHSA-N and UNII MB7V137HOF. Glucofrangulin B (PubChem CID 46173833) has the molecular formula C26H28O14.
A new anthraquinone glycoside isolated from fruits of R. prinoides was identified as emodin-1-O-β-D-glucopyranoside, 3-O-(1,2-di-O-acetyl-α-L-rhamnopyranoside), found together with emodin-1-O-β-D-glycopyranoside, 3-O-α-L-rhamnopyranoside (glucofrangulin A) and emodin glucoside B.
1.2 Botanical Source
The principal botanical sources of glucofrangulin are members of the Frangula and Rhamnus genera. Frangula alnus, commonly known as Alder Buckthorn, is the most well-documented and primary source of this compound. Scientifically known as Frangula alnus Mill. or Rhamnus frangula, this plant is a spontaneous shrub belonging to the Rhamnaceae family.
The plant is native to Europe from southern Scandinavia to North Africa, the Urals, and Siberia. This small tree, native to Europe and Central Asia, has also managed to spread to North Africa and was later naturalized in the eastern United States. It grows as a deciduous shrub or small tree, thriving particularly in humid places such as riverbanks, forest edges, and marshy areas, where it finds its ideal habitat up to about 1,000 meters in altitude.
Glucofrangulin has also been identified in other Rhamnus species. Glucofrangulin A diacetate has been isolated from the fruits of Rhamnus prinoides. The genus Rhamnus as a whole has received considerable interest as a source of phenolic chemicals.
1.3 Standard Content Requirements and Analytical Methods
Frangula bark must contain not less than 7.0 per cent of glucofrangulins, expressed as glucofrangulin A (C27H30O14; molecular weight 578.5), calculated with reference to the dried herbal substance, to comply with the European Pharmacopoeia monograph on "Frangula bark."
The dried bark (whole or fragmented) of the stems and branches of Rhamnus frangula L. (Frangula alnus Miller) must contain a minimum of 7.0% of glucofrangulins, expressed as frangulin A (dried drug), to meet EU Pharmacopoeia specifications. Frangula bark is also used as a starting material for the preparation of a dry standardized extract produced by ethanol extraction.
Validated HPLC and UHPLC methods for the quantitative determination of frangulins A and B and glucofrangulins A and B in the bark of Frangula alnus have been developed by researchers at the Zurich University of Applied Science. Glucofrangulin content in plant extracts has been reported in a range of 0.12 to 0.34%, a result considered acceptable given the complexity of whole plant extract and the variety of compounds present.
2. Key Constituents and Co-occurring Compounds in the Botanical Source
Glucofrangulin A and B are classified as emodin diglycosides. The frangula bark herbal substance also contains small quantities of other anthraquinone glycosides, dianthrones, and the aglycones emodin and emodin-9-anthrone.
Chrysophanol, emodin, and emodin dianthrone have been confirmed in the fresh bark of Rhamnus frangula. The drug of the plant is the cortex (bark), from which anthraquinone active ingredients such as mainly glucofrangulin A are extracted. In the cortex, small quantities of aglycones such as emodin and emodin-9-anthrone are also present.
Studies on the leaves of F. alnus have revealed five phenolic acids and four flavonoids, with rosmarinic acid and chlorogenic acid as the main phenolic acids, and quercitrin and trifolin as the major flavonoids.
In the fresh bark, the glucofrangulins are available in reduced form, while in the stored bark they are in oxidized form. With this oxidization, a saccharolytic process occurs and the stored bark therefore contains a higher amount of the simpler glycosides.
3. Traditional and Historical Use
3.1 European Herbal Medicine
The Greek physician Galen, in the 2nd century A.D., knew of alder buckthorn, although he did not clearly distinguish it in his writings from other closely related species. These plants were credited with the power to protect against witchcraft, demons, poisons, and headaches.
Frangula (Frangula alnus or Rhamnus frangula) has a long history of traditional use as a herbal remedy, particularly in Europe and North America. Its bark has been treasured since medieval times as a natural remedy, most notably serving as a laxative.
The dried bark of the plant contains anthraquinone glycosides, compounds known to have a laxative effect by stimulating bowel movements and increasing intestinal motility. This traditional use is well-documented in various herbal pharmacopeias and has been practiced in European herbal medicine for centuries.
3.2 Preparation of the Bark for Use
A central feature of the traditional use of frangula bark — and the source of glucofrangulin as a medicinal constituent — is the requirement for proper aging or drying before use. Fresh bark contains irritating substances (anthranols) potentially harmful to the intestines. For this reason, the bark must necessarily undergo a process of drying and aging for at least 1–2 years before use. This process allows the oxidation of anthranols into anthraquinones, making the bark safe and effective.
The bark (and to a lesser extent the fruit) has been used as a laxative, due to its 3–7% anthraquinone content. Bark for medicinal use is dried and stored for a year before use, as fresh bark is violently purgative; even dried bark can be dangerous if taken in excess.
Alternatively, the EMA notes that accelerated preparation is possible: the bark can be "dried in a dark place and heated for 2 hours at 100°C, or stored not less than 1 year from harvesting," in accordance with pharmacopoeial requirements.
Historically, the bark of the bush was also used for the production of gunpowder and charcoal.
3.3 Scope of Traditional Applications
The bark is laxative, cholagogue, and tonic, and was mainly used for chronic constipation. For a long time, the therapeutic uses of the bark's 1,8-dihydroxyanthraquinone derivatives were only laxative and purgative. For about 25 years, numerous scientific studies have also indicated antimicrobial, antifungal, and insecticidal activities after biological investigations.
4. Active Compounds and Mechanisms of Action
4.1 Colonic Bacterial Activation
The glycosides from frangula (like sennosides and rhubarb glycosides) are not absorbed in the upper gut; they are converted by bacteria of the large intestine into active metabolites. Glucofrangulin A and B are the main constituents of frangula bark with known therapeutic activity and belong to the anthraquinone O-glycosides. For glucofrangulin, it has been shown that the aglycone moieties are set free in the gut through bacterial β-glycosidases.
In the cortex, small quantities of aglycones such as emodin and emodin-9-anthrone are also present. Frangula belongs to the family of stimulant laxatives and emodin-9-anthrone is the main metabolite produced by the bacteria at the intestinal level.
4.2 Dual Mechanism of Laxative Action
The laxative action of glucofrangulin and its related compounds has been characterized as involving two distinct but complementary mechanisms:
- First, there is an influence on the motility of the large intestine — stimulation of peristaltic contractions and inhibition of local contractions — resulting in accelerated colonic transit and reduced fluid absorption.
- Second, frangula anthraquinones influence the secretion process by inhibiting the absorption of water and electrolytes in colonic epithelial cells, increasing the resistance of the tight junctions, and stimulating the secretion of water and electrolytes (Na⁺ and Cl⁻) into the colon lumen.
The bark contains anthraquinones which are inactive in the gastrointestinal tract until they reach the colon, where they are degraded by bacterial enzymes; within about six to eight hours this causes vigorous peristalsis.
Frangula bark predominantly contains the anthranoids as anthraquinones. Therefore, it is supposed that the influence of frangula bark on fluid absorption and on secretion processes is lower than the influence of other anthranoid-containing herbal substances.
4.3 Structure–Activity Considerations
The potency of anthranoid laxatives depends on the structure of the anthranoid molecule. Compounds containing a larger number of sugar molecules have a stronger effect. The most potent laxatives are anthrone and dianthrone compounds.
The bianthrones, especially sennosides, as found in rhubarb and senna, appear to be more active as laxatives than simple anthraquinones.
5. Scientific Evidence by Area of Use
5.1 Constipation — Animal Studies
The primary evidence base for glucofrangulin's laxative effect includes well-characterized animal studies. In investigations performed by Cressari et al. (1966), different constituents of frangula bark were evaluated for laxative effect in comparison to a standard senna leaves extract in mice. Glucofrangulin and frangulin only showed a laxative effect after oral administration. This effect was nearly 4 to 5 times stronger than the effect of the senna extract.
The administration of a methanolic extract of frangula bark (17.5% anthranoid glycosides calculated as 1,8-dihydroxyanthraquinone-glycoside) in mice resulted in a dose-dependent decrease of intestinal transit time. After oral administration of 50 mg/kg body weight, defecation after 4 hours occurred in 20% of the mice; after oral administration of 100 mg/kg body weight, defecation after 4 hours occurred in 40% of the mice.
Glucofrangulin and frangulin only showed a laxative effect after oral administration. This effect was nearly 4 to 5 times stronger than the effect of the senna extract used, although for glucofrangulin there were signs of a reduction concerning the relative effectiveness.
5.2 Constipation — Human/Clinical Evidence
As reported in the EMA plant monograph, the administration in humans of an aqueous suspension containing the equivalent of 12 mg of anthraquinone derivatives (glucofrangulin and frangulin) had a laxative effect within 6 to 24 hours. There are no clinical studies exclusively relating to the administration of frangula extracts, but only in combination with other active ingredients.
In its assessment, the HMPC considered a number of clinical studies with frangula bark in combination with other laxatives looking at its effectiveness in treating constipation. There are no recent studies evaluating frangula bark alone; therefore, the HMPC's conclusions on the effects of frangula bark to treat constipation are also based on experts' opinions, clinical experience, and clinical and laboratory studies obtained with other anthranoid-containing laxatives such as senna leaf preparations.
One combination study assessed the effect of a formulation (Laxariston) containing methylcellulose (0.9 g), extract of senna leaves (corresponding to 7.5 mg of hydroxyanthracene derivatives), extract of rhubarb root (equal to 6.75 mg of hydroxyanthracene derivatives), 15 mg of Achillea extract, and extract of frangula cortex containing an amount of hydroxyanthracene derivatives equal to 13.5 mg.
Evidence strength: The EMA/HMPC classifies frangula bark under the traditional use category rather than as a "well-established use" medicinal product, reflecting the absence of robust standalone randomized clinical trials for glucofrangulin or frangula bark alone. The laxative effects attributed to glucofrangulin are supported principally by animal studies, analogy with related anthranoid laxatives (e.g., senna), expert opinion, and limited combination-product human studies.
5.3 Antimicrobial Activity
Anthranoid compounds, including the glucofrangulins, have significant reported pharmacological properties. They show antioxidant, antibacterial, fungicidal, antiviral, and anticancer properties beyond their established use as laxatives.
One study revealed that bark extracts of F. alnus had strong antibacterial activities against Staphylococcus aureus. The bark has been widely investigated for its medicinal properties, especially its laxative effects and the bioactive properties of the plant material extract, though there is no wider study devoted specifically to its antibacterial properties.
Evidence strength: The antimicrobial evidence related to glucofrangulin as an isolated compound is preliminary and based primarily on in vitro or extract-level studies. No clinical trials exist for glucofrangulin as an isolated antimicrobial agent.
5.4 Antioxidant Activity
The antioxidant capacity of extracts containing glucofrangulins has been demonstrated through various assays, such as DPPH and ABTS radical scavenging. Bark extracts of Frangula alnus have shown moderate antioxidant capacity, which is linked to their high phenolic content.
In a published study, results on antioxidant activity showed that, unlike isolated emodin, bark extract possesses moderate antioxidant capacity (44.6%, 46.8% and 2.25 mmol Fe²⁺/g measured by DPPH, ABTS, and FRAP assay, respectively), attributable to a relatively high phenolic content of 116.07 mg/g.
Evidence strength: In vitro only. No clinical data exists for the antioxidant effects of glucofrangulin as an isolated compound in humans.
5.5 Anti-inflammatory Activity (Frangulin B — Related Compound)
The in vitro anti-inflammatory activities of the isolated anthraquinone frangulin B, from Rhamnus formosana, were assessed by determining its inhibitory effects on chemical mediators released from mast cells, neutrophils, macrophages, and microglial cells. Frangulin B showed potent inhibitory effects on TNF-alpha formation in LPS/IFN-gamma-stimulated murine microglial cell lines N9.
Evidence strength: These findings are based on in vitro cell-line studies for frangulin B, a closely related but chemically distinct monoglycoside compound. Data specific to glucofrangulin's anti-inflammatory activity is limited. No human data exists.
6. Body Systems and Health Areas of Association
6.1 Gastrointestinal System
The primary and best-established area of use for glucofrangulin is as a stimulant laxative acting on the large intestine. Glucofrangulin is a natural glycoside found in the bark of buckthorn (Frangula alnus) and belongs to the class of anthraquinones. Like frangulin, glucofrangulin is known for its mild laxative properties and is used medicinally to treat constipation. The action of glucofrangulin is to increase the secretion of water in the lumen of the intestinal tract and strengthen the contractions of its walls, causing fecal masses to be excreted from the body faster. Drugs containing glucofrangulin are usually used for short-term relief of constipation symptoms.
6.2 Immune and Microbial Systems
The emodin aglycone (1,6,8-trihydroxy-3-methyl-anthraquinone) released upon metabolic activation exhibits numerous reported biological activities, including effects on the immune system, repairing UV-induced DNA damage, acting on the vasomotor system, and having anti-inflammatory and analgesic effects. These effects have been documented primarily in in vitro and animal models.
7. Dosage Forms and Dosages Reported in Studies
7.1 Pharmacopoeial and Regulatory Dosage Guidance
The recommended dosage for adults, elderly individuals, and adolescents over 12 years as a laxative (20–30 mg hydroxyanthracene derivatives once daily at night) is supported by experts' opinions and by clinical investigations with other hydroxyanthracene-containing laxatives, notably preparations of senna and aloes. Following the approach in these monographs to minimize the amount used, the recommended range is 10–30 mg hydroxyanthracene derivatives daily.
As reported in the EMA plant monograph, the administration in humans of an aqueous suspension containing the equivalent of 12 mg of anthraquinone derivatives (glucofrangulin and frangulin) had a laxative effect in the following 6 to 24 hours.
Per the EU herbal monograph, frangula bark preparations are not to be used for more than 1 week.
7.2 Dosage Forms
The HMPC conclusions cover frangula bark preparations that are obtained by drying and comminuting (reducing into tiny pieces) the bark. The dried comminuted bark may also be put in a solvent (such as ethanol) to dissolve compounds and form an extract.
Anthranoid substances are very rarely administered in the form of isolated compounds or galenic preparations. In practice, glucofrangulin is consumed as a constituent of standardized herbal extracts (in tablet, capsule, or liquid extract form), herbal teas (decoctions), and combination-laxative products.
7.3 Animal Studies — Dose References
From in vivo studies in mice, the cortex extract with an anthraquinone glycoside titre of 17.5% reduced the time of intestinal transit and after administration, defecation occurred after 4 hours in a dose-dependent manner. After oral administration of 50 mg/kg body weight, defecation after 4 hours occurred in 20% of mice; after 100 mg/kg body weight, it occurred in 40% of mice.
8. Safety Considerations
8.1 Adverse Effects
Frangula bark may produce abdominal pain, spasm, and liquid stools, especially in patients with irritable colon. These side effects may occur due to overdosage.
Chronic use may lead to disorders in water equilibrium and electrolyte metabolism and may result in albuminuria and haematuria. Furthermore, chronic use may cause pigmentation of the intestinal mucosa (pseudomelanosis coli), which usually recedes when the treatment is stopped.
The adverse effects of laxative anthraquinone drugs are more likely to result from excessive loss of fluid and electrolytes, particularly potassium, associated with the use of high doses. Habituation is a result of the fact that chronic abuse of laxatives raises aldosterone levels in response to electrolyte loss, diminishing their effectiveness. Higher doses also empty a larger portion of the colon, and the resulting natural absence of defecation over the following day leads to renewed anthraquinone use.
8.2 Electrolyte Monitoring
Electrolytes, especially potassium, should be monitored during use. This is especially important in the elderly.
8.3 Genotoxicity and Carcinogenicity Concerns
The genotoxic potential of anthranoid constituents has been the subject of formal regulatory review. The EFSA ANS Panel (2018) concluded that "the hydroxyanthracenes, emodin, aloe-emodin and the structurally related substance danthron, have been shown to be genotoxic in vitro."
An investigation by Helmholz et al. (1993) examined the mutagenic and genotoxic activities of the glycosides emodin and frangulin and of an alcoholic extract of Rhamnus frangula. The anthranoid content of 1 g of the alcoholic extract was: 50.76 mg glucofrangulin, 86.84 mg frangulin, 30.88 mg emodin, 10.3 mg physcion, and 14.32 mg chrysophanol. The tests provided evidence of a dose-dependent increase in the mutation rate or the induction of DNA repair for the glycosides, the extract, and the commercial preparation. The mutagenic potency was larger for emodin than for the alcoholic extract than for frangulin.
Experimental data, mainly from in vitro tests, showed a genotoxic risk for several anthranoids (emodin, chrysophanol, and physcion). However, in vivo studies of the crude senna herbal substance showed no evidence of any genetic effects. In vitro assays are generally considered to overestimate the potential hazard from exposure and must be re-evaluated by in vivo experiments.
In 2001, the National Toxicology Program (NTP) of the U.S. Department of Health and Human Services published a technical report on toxicology and carcinogenesis studies of emodin.
One study found that a bark extract at 500 μg/ml produced cell death and DNA damage in human peripheral blood lymphocytes, while the level of ROS changed at 250 μg/ml. Emodin induced cell death at 150 μg/ml and DNA damage at 200 μg/ml, with increased ROS observed at 25 μg/ml. These results suggest that both bark extract and emodin are cyto/genotoxic to human peripheral blood lymphocytes and that oxidative stress is involved in the mechanism of their toxicity. These findings are based on in vitro cell culture models and do not directly translate to clinical toxicity at standard laxative doses.
In contrast, a prior study found that neither anthranoid laxative use, even in the long term, nor macroscopic or marked microscopic melanosis coli were associated with any significant risk for the development of colorectal adenoma or carcinoma.
8.4 Contraindications
The EU herbal monograph on Rhamnus frangula cortex lists hypersensitivity to the active substance and use in children under 12 years of age as contraindications. The EMA HMPC assessment also notes that frangula bark preparations should not be used in cases of intestinal obstruction and stenosis, atony, inflammatory colon diseases (e.g., Crohn's disease, ulcerative colitis), appendicitis, abdominal pain of unknown origin, and severe dehydration states.
8.5 Pregnancy and Lactation
No in vivo study on reproductive toxicity of frangula bark or frangula bark preparations is available. Regulatory authorities generally advise against the use of anthranoid-containing preparations during pregnancy and lactation due to insufficient data on reproductive safety.
8.6 Drug Interactions
The adverse effects of laxative anthraquinone drugs are more likely to result from excessive loss of fluid and electrolytes, particularly potassium, associated with the use of high doses. This electrolyte loss is of particular clinical relevance when frangula bark preparations are co-administered with:
- Cardiac glycosides — hypokalemia induced by chronic use can potentiate the effects of cardiac glycosides such as digoxin.
- Antiarrhythmic drugs — hypokalemia can affect the QT interval and interact with antiarrhythmics.
- Corticosteroids and diuretics — may increase the risk of electrolyte imbalance when combined with anthraquinone-containing laxatives.
These interaction risks are noted in the EMA/HMPC assessment framework for anthranoid-containing herbal laxatives as a class. Potassium levels should be monitored, especially in elderly patients.
8.7 Duration of Use
Long-term use as a laxative is not advised as dependence may result. Long-term use of laxatives should be avoided, because of possible laxative dependence (stimulated peristalsis begins to replace natural peristalsis), and because it may produce a harmful effect on intestinal mucosa which leads to a condition known as melanosis coli (or pseudomelanosis).
9. Regulatory and Pharmacopoeial Status
The European Medicines Agency's Committee on Herbal Medicinal Products (HMPC) has issued scientific conclusions on the medicinal uses of frangula bark. The HMPC conclusions are taken into account by EU Member States when evaluating applications for the licensing of herbal medicines containing frangula bark.
Glucofrangulin A is the substance used as a reference for the standardization of frangula preparations included in the EU Pharmacopoeia. The plant's bark is listed in the European Pharmacopoeia under the official monograph "Frangulae cortex." The EMA HMPC assessment classifies frangula bark preparations as a traditional herbal medicinal product for the treatment of occasional constipation, reflecting the traditional rather than well-established evidence base.
Frangulin and glucofrangulin from frangula bark are classified in pharmacognosy texts within the laxative group of anthraquinone glycosides, alongside sennosides from senna and cascarosides from cascara bark.
References
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