Bismuth subgallate

Identification

Name
Bismuth subgallate
Accession Number
DB13909
Type
Small Molecule
Groups
Approved
Description

Bismuth subgallate is a yellow colored substance that presents as an odorless powder that undergoes discoloration when exposed to sunlight. It is a heavy metal salt of gallic acid that is highly insoluble and poorly absorbed. Possessing protective effects on the gastric mucosa, strong astringent effects, and not as yet elucidated antimicrobial and hemostatic actions, bismuth subgallate is most commonly available as an over-the-counter internal deodorant where it is often employed as the primary active ingredient.

Structure
Thumb
Synonyms
  • basic bismuth 3,4,5-trihydroxybenzoate
  • basisches Wismutgallat
  • Bismuth subgallate
  • Bismuto subgalato
  • gallic acid bismuth basic salt
  • Wismutgallathydroxid
Prescription Products
NameDosageStrengthRouteLabellerMarketing StartMarketing End
Stomax - Tab 400mgTablet400 mgOralHope PharmaceuticalsNot applicableNot applicableCanada
Over the Counter Products
NameDosageStrengthRouteLabellerMarketing StartMarketing End
Devrom Chew Tab 200mgTablet, chewable200 mgOralThe Parthenon Company Inc.1978-12-31Not applicableCanada
International/Other Brands
Dermatol
Categories
UNII
YIW503MI7V
CAS number
99-26-3
Weight
Average: 394.091
Monoisotopic: 393.98901
Chemical Formula
C7H5BiO6
InChI Key
JAONZGLTYYUPCT-UHFFFAOYSA-K
InChI
InChI=1S/C7H6O5.Bi.H2O/c8-4-1-3(7(11)12)2-5(9)6(4)10;;/h1-2,8-10H,(H,11,12);;1H2/q;+3;/p-3
IUPAC Name
2,7-dihydroxy-2H-benzo[d]1,3-dioxa-2-bismacyclopentane-5-carboxylic acid
SMILES
O[Bi]1OC2=CC(=CC(O)=C2O1)C(O)=O

Pharmacology

Indication

The most common medical purpose for which bismuth subgallate is currently and formally indicated for is the use as a non-prescription internal deodorant product for the purpose of deodorizing flatulence and stools [12, 13, 1].

Additionally, there are also various non-prescription (over the counter) bismuth subgallate based wound healing products as well as ongoing studies into whether or not the substance can be utilized as a legitimate hemostatic agent - usually for soft tissue surgery in otorhinolaryngology and/or dermatologic settings [2, 3, 4, 5].

Moreover, in the past bismuth subgallate may have seen some use as a treatment for Helicobacter pylori infection [6]. In contrast, contemporary first-line therapies generally involve proton pump inhibitor and antibiotic combination therapies that generally achieve high rates of pathogen eradication, ease of administration, and patient compliance.

Associated Conditions
Pharmacodynamics

Bismuth subgallate is a heavy metal salt that is relatively insoluble and poorly absorbed [4, 14]. As a result, systemic absorption is not necessary [14] or possibly even desired when the agent is administered orally or onto specific otorhinolaryngology and/or dermatologic wound sites where it can execute its pharmacologic action directly within the gastrointestinal lumen [14] to deodorize flatulence and stools or potentially elicit a hemostatic effect on wounds [4].

Additionally, like other bismuth agents, one of the most common side effects associated with bismuth subgallate is its propensity to cause a black discoloration of the tongue and stools when the agent combines with trace amounts of sulfur in the saliva and/or gastrointestinal tract [15]. This discoloration is temporary and harmless, gradually dissipating over a number of days and eventually disappearing after the discontinuation of the bismuth agent [15].

Mechanism of action

Bismuth salts exert their action largely in the upper gastrointestinal tract by way of local activity from luminal bismuth in the stomach and duodenum [6].

In terms of bismuth subgallate's ability to deodorize flatulence and stools as an internal deodorant - although not fully elucidated - it is believed that when the substance is administered orally, its relative insolubility and poor absorption allows it to remain within the gastrointestinal lumen and inhibit colonic bacteria from acting on fermentable food residues in the GI tract [14].

Moreover, when bismuth subgallate is taken orally, various salts like bismuth citrate, bismuth oxychloride, and others are formed [6]. These salts are then taken up into surrounding gastric mucus as well as bound to protein within the base of any ulcers that may be present after coming into contact with gastric juice [6]. Additionally, bismuth compounds like bismuth subgallate are also believed to have the capacity to trigger the secretion of prostaglandins, epithelial growth factor (EGF), and mucosal bicarbonate as a means to inhibit the action of pepsin in gastric juice [6]. These actions subsequently protect gastric mucous from peptic luminal degradation as well as enhance the properties of mucous to assist in the healing of both duodenal and gastric ulcers [6]. In this way, bismuth subgallate works to absorb extra water and/or toxins in the large intestine, allowing it to form a protective coat on the intestinal mucosa and over ulcers that may or may not be associated with infections like those of Helicobacter pylori [13].

Furthermore, studies have shown that bismuth compounds like bismuth subgallate are capable of demonstrating antimicrobial effects against various gastrointestinal tract pathogens like E. coli, Salmonella, Shigella, Vibrio cholera, Campylobacter jejuni, H. pylori, and some enteric viruses like Rotaviruses [6]. Although the exact mechanism(s) of action by which bismuth compounds are able to elicit such antimicrobial effects remains unclear [6], a number of experimental observations suggest that bismuth has been able to complex with the bacterial wall and periplasmic membrane; inhibit bacterial enzymes like urease, catalase, and lipase; inhibit bacterial protein and ATP synthesis; and also inhibit or decrease the adherence of bacteria like H. pylori to epithelial cells [6]. In essence, ultrastructural studies have shown evidence of the binding of bismuth complexes to the bacterial wall and periplasmic space between the inner and outer bacterial membrane of H.pylori with subsequent ballooning and disintegration of the pathogen [6]. To various extents, these antimicrobial actions may also illustrate how bismuth subgallate is capable of neutralizing colonic bacteria from acting on fermentable foods as well.

Numerous studies have and continue to study the possible hemostatic action that bismuth subgallate may have. As the bismuth salt of gallic acid, bismuth subgallate's chemical structure shares similarities to ellagic acid, another gallic acid derivative [7]. Ellagic acid itself is a clot-promoting agent that initiates thrombin formation by way of the intrinsic pathway via an action on Hageman factor (clotting factor XII) [7, 4]. It is believed that bismuth subgallate's ability to activate factor XII is associated with the chemical's negatively charged moieties - whose contact with factor XII would theoretically initiate the intrinsic pathway to blood clotting [7].

Other studies have also suggested that bismuth subgallate is capable of inducing macrophages to secrete growth factors to facilitate wound healing, decreasing lesion area, enhancing granulation tissue formation and re-epithelialization, the initiation of the proliferation of collagen via the activation of fibroblasts, the accelerated re-establishment of blood vessels, and also the restriction of nitric oxide formation [5, 8].

Given such studies regarding bismuth subgallate's potential hemostatic abilities, there has been and continues to be interest in indicating the agent for use in otolaryngology as in tonsillectomies or adenotonsillectomies to achieve reduced bleeding and surgery times; topical treatment in various open wound surgeries to facilitate faster and earlier clotting between tissues; ileostomy; dental surgeries; epistaxis management; among others [2, 4]. Nevertheless, study results are conflicting; where there may be experimental results suggesting some improvements in reduced operation time and operative blood loss when bismuth subgallate is used as a hemostatic agent in tonsillectomies [7] there are also study results that observed bismuth subgallate having a negative influence on the healing processes of wounds inflicted in animal models, in which the use of the agent actually delayed the rate of new vessel formation and optimal wound healing [4].

Finally, bismuth subgallate also demonstrates a strong astringent ability [4] - an action that can facilitate both its deodorant and hemostatic effects and assists in its indication as an active ingredient in a number of non-prescription products for hemorrhoid suppositories or topical applications, diarrhea, etc [14].

Absorption

Bismuth subgallate is only slightly, if at all, absorbed after oral ingestion [14]. The general human oral bioavailability of bismuth subgallate has been reported as low as 0.04% [14]. Any absorption that does occur is likely to happen from the upper small intestine [6].

The gastrointestinal absorption of bismuth from bismuth compounds demonstrates a large interindividual variation [14]. Factors affecting the absorption involve the formulation of the bismuth subgallate compound as well as the dietary factors of the individuals themselves [6]. Nevertheless, absorption can be enhanced with the concomitant intake of citrate and sulfhydryl-group-containing compounds [14]. Conversely, the simultaneous administration of antacids or a diet that is high in thiol content can lower absorption of bismuth subgallate [6].

Volume of distribution

In general, oral administration is one of the most common routes of administration for non-prescription bismuth subgallate products and gastrointestinal and systemic absorption is usually very low.

Protein binding

In general, any systemic absorption of bismuth subgallate is expected to be low but any bismuth that is absorbed is also expected to bind to plasma proteins [6] and be distributed throughout all tissues [6], with the highest concentration found in the kidney [14, 6] and lower levels in the lung, spleen, liver, brain, bone, and muscle [14].

The bismuth component itself is generally known to demonstrate a high percentage binding to plasma proteins of >90% [16].

Metabolism

No specific metabolism of bismuth is known [14]. In the kidney it induces the de novo synthesis of a bismuth-metal-binding protein, which is a kind of methallothionein [14].

Route of elimination

Ingested bismuth is primarily eliminated unabsorbed by way of the faeces [14]. Any absorbed bismuth is eliminated from the body by both the urinary and faecal (including bile) routes [14]. Excretion of absorbed bismuth in the urine is rapid, with most of the metal excreted within 24 hours [6]. About 10% of the absorbed bismuth is detected in faeces, presumably owing to biliary secretion [6].

Half life

The bismuth component of bismuth subgallate is known to have a terminal half-life of 21-72 days [16].

Clearance

On average, the blood clearance of the bismuth component of a bismuth salt like bismuth subgallate is within the range of 50 to 95 ml/min [9].

Toxicity

Depending on the level of severity of a patient's renal impairment, administration of bismuth compounds may not be appropriate as the reduced renal clearance can lead to undesirably elevated blood levels of bismuth [6]. Similarly, because of the biliary excretion of bismuth, severe liver disease may theoretically result in accumulation of bismuth as well [6].

Bismuth toxicity seemingly develops only from excessive dosage (perhaps from ingestion of bismuth over a prolonged time or intramuscular injections) and is characterized by nephrotoxicity, osteoarthropathy, encephalopathy, hepatotoxicity, stomatitis, and gingivitis [6]. However, the insoluble inorganic bismuth compounds are reported to be mainly associated with reversible encephalopathy [6]. In fact a number of studies have discussed how patients may experience a syndrome of subacute, progressive encephalopathy involving potential aphasia, myoclonous, and/or gait instability after taking bismuth subgallate in large quantities well over the usual recommended dosages [10, 11]. This kind of encephalopathy is usually reversible with the discontinuation of the bismuth subgallate usage however [10, 11].

Affected organisms
  • Humans and other mammals
Pathways
Not Available
Pharmacogenomic Effects/ADRs
Not Available

Interactions

Drug Interactions
DrugInteraction
AbacavirAbacavir may decrease the excretion rate of Bismuth subgallate which could result in a higher serum level.
AcarboseAcarbose may decrease the excretion rate of Bismuth subgallate which could result in a higher serum level.
AceclofenacAceclofenac may decrease the excretion rate of Bismuth subgallate which could result in a higher serum level.
AcemetacinAcemetacin may decrease the excretion rate of Bismuth subgallate which could result in a higher serum level.
AcepromazineAcepromazine may increase the neurotoxic activities of Bismuth subgallate.
AceprometazineAceprometazine may increase the neurotoxic activities of Bismuth subgallate.
AcetaminophenAcetaminophen may decrease the excretion rate of Bismuth subgallate which could result in a higher serum level.
AcetazolamideAcetazolamide may increase the excretion rate of Bismuth subgallate which could result in a lower serum level and potentially a reduction in efficacy.
AcetophenazineAcetophenazine may increase the neurotoxic activities of Bismuth subgallate.
Acetylsalicylic acidAcetylsalicylic acid may decrease the excretion rate of Bismuth subgallate which could result in a higher serum level.
Food Interactions
Not Available

References

General References
  1. Sparberg M: Correspondence: Bismuth subgallate as an effective means for the control of ileostomy odor: a double blind study. Gastroenterology. 1974 Mar;66(3):476. [PubMed:4813513]
  2. Tramontina VA, Machado MA, Nogueira Filho Gda R, Kim SH, Vizzioli MR, Toledo Sd: Effect of bismuth subgallate (local hemostatic agent) on wound healing in rats. Histological and histometric findings. Braz Dent J. 2002;13(1):11-6. [PubMed:11870955]
  3. Puia SA, Renou SJ, Rey EA, Guglielmotti MB, Bozzini CE: Effect of bismuth subgallate (a hemostatic agent) on bone repair; a histologic, radiographic and histomorphometric study in rats. Int J Oral Maxillofac Surg. 2009 Jul;38(7):785-9. doi: 10.1016/j.ijom.2009.03.003. Epub 2009 Apr 16. [PubMed:19375279]
  4. Couto EV, Ballin CR, Sampaio CP, Maeda CA, Ballin CH, Dassi CS, Miura LY: Experimental study on the effects of bismuth subgallate on the inflammatory process and angiogenesis of the oral mucosa. Braz J Otorhinolaryngol. 2016 Jan-Feb;82(1):17-25. doi: 10.1016/j.bjorl.2014.12.009. Epub 2015 Oct 27. [PubMed:26614041]
  5. Mai LM, Lin CY, Chen CY, Tsai YC: Synergistic effect of bismuth subgallate and borneol, the major components of Sulbogin, on the healing of skin wound. Biomaterials. 2003 Aug;24(18):3005-12. [PubMed:12895572]
  6. Lambert JR, Midolo P: The actions of bismuth in the treatment of Helicobacter pylori infection. Aliment Pharmacol Ther. 1997 Apr;11 Suppl 1:27-33. [PubMed:9146788]
  7. Agrawal SR, Jain AK, Marathe D, Agrawal R: The effect of bismuth subgallate as haemostatic agent in tonsillectomy. Indian J Otolaryngol Head Neck Surg. 2005 Oct;57(4):287-9. doi: 10.1007/BF02907688. [PubMed:23120195]
  8. Vyas KS, Vasconez HC: Wound Healing: Biologics, Skin Substitutes, Biomembranes and Scaffolds. Healthcare (Basel). 2014 Sep 10;2(3):356-400. doi: 10.3390/healthcare2030356. [PubMed:27429283]
  9. Benet LZ: Safety and pharmacokinetics: colloidal bismuth subcitrate. Scand J Gastroenterol Suppl. 1991;185:29-35. [PubMed:1957122]
  10. Sampognaro P, Vo KT, Richie M, Blanc PD, Keenan K: Bismuth Subgallate Toxicity in the Age of Online Supplement Use. Neurologist. 2017 Nov;22(6):237-240. doi: 10.1097/NRL.0000000000000144. [PubMed:29095326]
  11. Burns R, Thomas DW, Barron VJ: Reversible encephalopathy possibly associated with bismuth subgallate ingestion. Br Med J. 1974 Feb 9;1(5901):220-3. [PubMed:4818163]
  12. Devrom Internal Deodorant (200 mg bismuth sabgallate) [Link]
  13. Drugs.com: Bismuth Subgallate Monograph [Link]
  14. COMMITTEE FOR VETERINARY MEDICINAL PRODUCTS: BISMUTH SUBNITRATE, BISMUTH SUBCARBONATE, BISMUTH SUBGALLATE, BISMUTH SUBSALICYLATE [Link]
  15. Pepto-Bismol: Why does Pepto-Bismol sometimes darken the tongue/stool and how long does it last? [Link]
  16. ScienceDirect: Bismuth subgallate [Link]
External Links
KEGG Drug
D01398
ChemSpider
10607905
ChEBI
31292
ChEMBL
CHEMBL1592101
Wikipedia
Bismuth_subgallate
MSDS
Download (47.3 KB)

Clinical Trials

Clinical Trials
Not Available

Pharmacoeconomics

Manufacturers
Not Available
Packagers
Not Available
Dosage forms
FormRouteStrength
Tablet, chewableOral200 mg
TabletOral400 mg
Prices
Not Available
Patents
Not Available

Properties

State
Solid
Experimental Properties
PropertyValueSource
water solubilityInsoluble in cold water and hot water.MSDS
Predicted Properties
PropertyValueSource
Water Solubility44.8 mg/mLALOGPS
logP0.4ALOGPS
logP0.55ChemAxon
logS-0.94ALOGPS
pKa (Strongest Acidic)3.93ChemAxon
pKa (Strongest Basic)-2.3ChemAxon
Physiological Charge-1ChemAxon
Hydrogen Acceptor Count6ChemAxon
Hydrogen Donor Count3ChemAxon
Polar Surface Area96.22 Å2ChemAxon
Rotatable Bond Count1ChemAxon
Refractivity39.39 m3·mol-1ChemAxon
Polarizability17.9 Å3ChemAxon
Number of Rings2ChemAxon
Bioavailability1ChemAxon
Rule of FiveYesChemAxon
Ghose FilterNoChemAxon
Veber's RuleNoChemAxon
MDDR-like RuleNoChemAxon
Predicted ADMET features
Not Available

Spectra

Mass Spec (NIST)
Not Available
Spectra
SpectrumSpectrum TypeSplash Key
Predicted MS/MS Spectrum - 10V, Positive (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 20V, Positive (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 40V, Positive (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 10V, Negative (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 20V, Negative (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 40V, Negative (Annotated)Predicted LC-MS/MSNot Available

Taxonomy

Description
This compound belongs to the class of organic compounds known as gallic acid and derivatives. These are compounds containing a 3,4,5-trihydroxybenzoic acid moiety.
Kingdom
Organic compounds
Super Class
Benzenoids
Class
Benzene and substituted derivatives
Sub Class
Benzoic acids and derivatives
Direct Parent
Gallic acid and derivatives
Alternative Parents
Benzoic acids / Benzoyl derivatives / Phenoxides / 1-hydroxy-4-unsubstituted benzenoids / 1-hydroxy-2-unsubstituted benzenoids / Monocarboxylic acids and derivatives / Carboxylic acids / Organooxygen compounds / Organic salts / Organic oxoanionic compounds
show 2 more
Substituents
Gallic acid or derivatives / Benzoic acid / Benzoyl / 1-hydroxy-4-unsubstituted benzenoid / 1-hydroxy-2-unsubstituted benzenoid / Phenoxide / Phenol / Carboxylic acid derivative / Carboxylic acid / Monocarboxylic acid or derivatives
show 7 more
Molecular Framework
Aromatic homomonocyclic compounds
External Descriptors
bismuth coordination entity (CHEBI:31292)

Carriers

Kind
Protein
Organism
Human
Pharmacological action
Unknown
Actions
Carrier
General Function
Toxic substance binding
Specific Function
Serum albumin, the main protein of plasma, has a good binding capacity for water, Ca(2+), Na(+), K(+), fatty acids, hormones, bilirubin and drugs. Its main function is the regulation of the colloid...
Gene Name
ALB
Uniprot ID
P02768
Uniprot Name
Serum albumin
Molecular Weight
69365.94 Da
References
  1. Lambert JR, Midolo P: The actions of bismuth in the treatment of Helicobacter pylori infection. Aliment Pharmacol Ther. 1997 Apr;11 Suppl 1:27-33. [PubMed:9146788]

Drug created on September 18, 2017 14:57 / Updated on December 16, 2018 07:01