Bismuth subsalicylate functions through multiple mechanisms to exert its antidiarrheal and gastroprotective effects. It works by forming a protective coating on the lining of the stomach and intestines, which helps to reduce irritation and inflammation. The compound also inhibits prostaglandin G/H synthase 1/2 (COX-1/2), thereby reducing the synthesis of prostaglandins that mediate inflammation in the gastrointestinal tract. This anti-inflammatory effect contributes to its ability to reduce gastric and intestinal mucosal inflammation. Bismuth subsalicylate also has the ability to inhibit the growth of certain bacteria, which can contribute to its anti-diarrheal effects. At the molecular level, bismuth subsalicylate interacts with the mucosal lining of the gastrointestinal tract, forming a barrier that helps to alleviate symptoms of indigestion and diarrhea. In vitro experiments suggest that bismuth subsalicylate inhibits the proteolytic action of pepsin by interacting with pepsin, rather than with the pepsin substrate. This indicates that bismuth subsalicylate can protect the esophageal mucosa against peptic injury, probably through inactivation of pepsin. The compound's antisecretory and antimicrobial mechanisms of action make it effective for the treatment of diarrhea.

In vitro, bismuth subsalicylate exhibits antibacterial and gastroprotective properties. It inhibits the growth of certain bacteria, which contributes to its anti-diarrheal effects. The compound also inhibits the proteolytic action of pepsin by interacting with pepsin, rather than with the pepsin substrate. This suggests that bismuth subsalicylate can protect the esophageal mucosa against peptic injury. The compound's inhibition of prostaglandin synthesis has been demonstrated in vitro using enzyme activity assays. Bismuth subsalicylate reduces gastric and intestinal mucosal inflammation through inhibition of prostaglandin synthesis. These in vitro studies provide a mechanistic basis for the compound's antidiarrheal and gastroprotective effects.

Salicylic acid and insoluble bismuth salts are produced in the gastrointestinal system from bismuth subsalicylate. Salicylic acid inhibits prostaglandin G/H synthase 1/2, which lowers inflammation and irritation of the stomach and intestinal walls [1]. Bismuth subsalicylate (oral gavage; 100 mg/kg-350 mg/kg) lowers fecal output (dry weight or wet weight) and the frequency of diarrhea in mice. It also dramatically lessens the transportation of charcoal test meals down the small intestine in mice and rats when exposed to castor oil [2].
In vivo, bismuth subsalicylate is an effective oral antacid and anti-diarrheal agent. It reduces inflammation and irritation of the stomach and intestinal lining through inhibition of prostaglandin synthesis. In animal models, bismuth subsalicylate significantly decreases castor oil-induced intestinal motility and reduces both fecal output and the frequency of diarrhea in mice. The compound forms a protective coating on the lining of the stomach and intestines, which helps to reduce irritation and inflammation. Bismuth subsalicylate is converted in the gastrointestinal tract to salicylic acid and insoluble bismuth salts. The salicylic acid component is absorbed and exerts systemic anti-inflammatory effects, while the bismuth component remains largely in the gastrointestinal tract and exerts local protective and antimicrobial effects. The compound is widely used for the research of diarrheal disorders, including indigestion, diarrhea, and nausea.

In vitro enzyme/receptor binding assays for bismuth subsalicylate involve measuring inhibition of prostaglandin G/H synthase 1/2 (COX-1/2) activity. In these assays, the enzyme is incubated with arachidonic acid substrate and varying concentrations of bismuth subsalicylate, and the production of prostaglandin products is measured using ELISA or radiometric methods. The compound's inhibition of pepsin activity is assessed by incubating pepsin with a protein substrate in the presence of bismuth subsalicylate and measuring the extent of proteolysis. These enzyme assays provide insights into the molecular mechanisms underlying the compound's anti-inflammatory and gastroprotective effects.

In vitro cell-based assays for bismuth subsalicylate evaluate its effects on gastrointestinal epithelial cells. Cells are cultured in appropriate media and treated with bismuth subsalicylate at various concentrations. The compound's cytoprotective effects are assessed by measuring cell viability after exposure to damaging agents such as acid, ethanol, or bile salts. Prostaglandin synthesis inhibition is measured by quantifying prostaglandin E2 production using ELISA. The compound's effects on cell signaling pathways, including NF-κB and MAPK pathways, are evaluated using Western blot and reporter gene assays. These cell-based assays provide critical information on the compound's cellular effects and its potential for modulating inflammation and protecting the gastrointestinal mucosa.

In vivo, bismuth subsalicylate is evaluated in rodent models of diarrhea, such as the castor oil-induced diarrhea model. Animals are treated with bismuth subsalicylate orally at various doses, and fecal output, frequency of diarrhea, and intestinal motility are measured. The compound's gastroprotective effects are evaluated in models of gastric ulceration, such as the ethanol-induced or indomethacin-induced ulcer models. In these models, animals are treated with bismuth subsalicylate prior to ulcer induction, and ulcer indices are calculated based on the number and severity of gastric lesions. Pharmacokinetic studies in animals involve administering bismuth subsalicylate and measuring salicylic acid and bismuth levels in blood and tissues using HPLC or atomic absorption spectroscopy. These animal studies are essential for establishing the compound's efficacy, safety, and pharmacokinetic profile.

Absorption, Distribution and Excretion
Following oral administration, bismuth subsalicylate is hydrolyzed in the stomach to bismuth and salicylic acid. Salicylic acid is almost completely absorbed in the small intestine, reaching peak plasma concentrations 1 to 2 hours after administration. In a study of healthy male subjects, after oral administration of 60 mL Pepto-Bismol (a common over-the-counter bismuth subsalicylate product, equivalent to 1050 mg of bismuth subsalicylate), the peak plasma concentration of salicylic acid was 40.1 μg/mL, with a time to peak concentration (Tmax) of 1.8 hours. Less than 1% of the bismuth subsalicylate is absorbed from the gastrointestinal tract into systemic circulation. In one study, after two weeks of oral administration of 787 mg bismuth subsalicylate chewable tablets, the mean glutar bismuth concentration was 5.1 ± 3.1 ng/mL. In another study, after oral administration of 525 mg bismuth subsalicylate liquid suspension, the mean glutar bismuth concentration ranged from 5 to 32 ng/mL.
After oral administration, the salicylate released from bismuth hyposalicylate is excreted in the urine. Bismuth is primarily excreted via urine and bile.
Currently, there is no relevant information.
The renal clearance of bismuth is 50 ± 18 mL/min.
The distribution of bismuth in autopsies of 22 patients who received therapeutic intramuscular injections (mainly bismuth salicylate) is as follows (median, mg/kg, wet weight): kidney 33.3; liver 6.8; spleen 1.6; colon 1.2; lung 0.9; brain 0.6; blood 0.5.
In the gastrointestinal tract, bismuth hyposalicylate is converted to salicylic acid and insoluble bismuth salts. A significant portion (over 90%) of the salicylate in bismuth hyposalicylate is absorbed and excreted in the urine. Bismuth hyposalicylate (bismuth salicylate) hydrolyzes in the gastrointestinal tract to bismuth salts and sodium salicylate. Two tablets or 30 mL of a suspension of this compound yield 204 mg and 258 mg of salicylate, respectively. Compared to organic bismuth compounds, inorganic bismuth salts have poorer water solubility and systemic absorption, but salicylates are still significantly absorbed. A brief study in 1992 found that 12 healthy subjects absorbed very little bismuth from bismuth hyposalicylate (serum concentrations were not specified), while one patient who took 216 mg of colloidal bismuth subcitrate experienced a peak serum bismuth concentration of 0.050 μg/ml. Studies have documented that some bismuth can be absorbed through the normal gastric mucosa, but the main absorption occurs in the duodenum.

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Metabolism/Metabolites
Bismuth hyposalicylate is hydrolyzed at pH less than 3. In the stomach, it is primarily hydrolyzed to bismuth oxychloride and salicylic acid. In the small intestine, unmetabolized bismuth hyposalicylate reacts with other anions (such as bicarbonate and phosphate) to form insoluble bismuth salts. In the colon, unmetabolized bismuth subsalicylate and other bismuth salts react with hydrogen sulfide produced by anaerobic bacteria to form bismuth sulfide, a highly insoluble black salt that causes dark stool color.
Biological Half-Life
After a single oral dose of 525 mg bismuth subsalicylate, the terminal half-life of salicylic acid is 2 to 5 hours. The intermediate half-life of bismuth is 5 to 11 days, and the terminal half-life is 21 to 72 days.
Bismuth subsalicylate is poorly absorbed from the gastrointestinal tract. After oral administration, the compound is converted in the gastrointestinal tract to salicylic acid and insoluble bismuth salts. Salicylic acid is absorbed and undergoes hepatic metabolism, primarily by conjugation with glycine to form salicyluric acid and by glucuronidation. The absorbed salicylic acid is distributed to various tissues and excreted primarily in urine. Bismuth is poorly absorbed and is excreted in feces. The compound's low systemic absorption minimizes the risk of systemic toxicity, although salicylic acid absorption can lead to salicylate-related side effects at high doses or with prolonged use. Bismuth subsalicylate's pharmacokinetics are characterized by low bioavailability of bismuth and variable absorption of salicylic acid.

Effects During Pregnancy and Lactation
◉ Overview of Medication Use During Lactation
Because infants may absorb salicylates through breast milk, alternative therapies are recommended.
◉ Effects on Breastfed Infants
There has been a case report of a 16-day-old breastfed infant developing metabolic acidosis after taking salicylates. The infant's mother was taking 650 mg of aspirin every 4 hours for arthritis. However, the case report did not test for salicylates in the mother's serum or breast milk, so it is unclear whether the infant directly ingested salicylates.
◉ Effects on Lactation and Breast Milk
As of the revision date, no relevant published information was found.
Protein Binding

The plasma protein binding rate of salicylic acid is approximately 90%. Bismuth has a plasma protein binding rate of over 90%.

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Interactions
When bismuth subsalicylate is taken concomitantly before or in a multiple-dose regimen with doxycycline, the bioavailability of doxycycline is significantly reduced by 37% and 51%, respectively. Bismuth subsalicylate should not be taken when doxycycline is used for therapeutic purposes.

Bismuth subsalicylate has a favorable safety profile when used at recommended doses for short-term treatment of diarrhea and indigestion. Common side effects include darkening of the tongue and stool, which are harmless and reversible upon discontinuation of the drug. The salicylic acid component can cause salicylate-related side effects, including tinnitus, nausea, and gastrointestinal irritation, particularly at high doses or with prolonged use. Bismuth toxicity is rare due to the compound's poor absorption, but prolonged high-dose use can lead to bismuth encephalopathy, a serious neurological condition characterized by confusion, ataxia, and myoclonus. The compound should be used with caution in patients with renal impairment, as reduced clearance of bismuth and salicylic acid can increase the risk of toxicity. In children and adolescents with viral infections, there is a theoretical risk of Reye's syndrome due to the salicylate component, although this risk is low with bismuth subsalicylate.

[1]. Bismuth subsalicylate. Drug.bank.

[2]. Mucoadhesive effect of Curcuma longa extract and curcumin decreases the ranitidine effect, but not bismuth subsalicylate on ethanol-induced ulcer model. Sci Rep. 2019 Nov 12;9(1):16622.

Therapeutic Uses
Used as an intestinal absorbent. Veterinary Uses: Antidiarrheal. It has a weak intestinal disinfectant effect due to the release of salicylic acid. It is usually used in combination with carbonates to minimize the irritation of free acid while utilizing the protective effect of bismuth. CMPD is sometimes used orally to relieve diarrhea or soothe gastritis or peptic ulcers. Before the advent of penicillin, bismuth subsalicylate was widely used to treat syphilis…
/SRP: Formerly/Treatment of Vincent's pharyngitis, syphilis
For more complete data on the therapeutic uses of bismuth subsalicylate (7 types), please visit the HSDB records page. Drug Warnings Even in cases of widespread use, gradual intramuscular injection therapy for the treatment of syphilis rarely results in serious poisoning. Treatment is usually discontinued if gingivitis, proteinuria, rash, or significant diarrhea occurs.
When bismuth subsalicylate was taken concurrently with doxycycline or in a multi-dose regimen, the bioavailability of doxycycline was significantly reduced by 37% and 51%, respectively. Bismuth subsalicylate should not be taken while being treated with doxycycline. The authors advise travelers not to take these medications concurrently to prevent diarrhea.
Because bismuth is poorly absorbed in the systemic circulation, no significant amount of bismuth subsalicylate is expected to be excreted into breast milk. However, salicylates are excreted into breast milk, and are cleared from breast milk more slowly than from plasma, with the milk/plasma ratio increasing from 0.03–0.08 at 3 hours to 0.34 at 12 hours. Given the potential adverse effects on nursing infants, the American Academy of Pediatrics recommends caution when using salicylates during breastfeeding. A recent review also noted that bismuth subsalicylate should be avoided during breastfeeding due to systemic absorption of salicylates.
Although the toxicity risk may be small, prolonged exposure to salicylates can lead to serious adverse reactions in the fetus. Therefore, bismuth subsalicylate use during pregnancy should be limited to the first half of pregnancy, and the dosage should not exceed the recommended dose.

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Pharmacodynamics
Bismuth subsalicylate has antacid, antibacterial, gastroprotective, acid-suppressing, and anti-inflammatory effects. It can reduce the severity and incidence of flatulence and diarrhea, thereby relieving gastrointestinal discomfort. One study showed that bismuth subsalicylate has a prevention rate of over 60% against traveler's diarrhea. The organic bismuth compounds formed by the breakdown of bismuth subsalicylate in the gastrointestinal tract can inhibit the growth of Helicobacter pylori and other bacteria associated with gastrointestinal diseases, as well as certain fungi. One study showed that when bismuth subsalicylate is used as part of a quadruple therapy containing a proton pump inhibitor, tetracycline, and metronidazole, it can eradicate up to 90% of Helicobacter pylori infection. Bismuth subsalicylate also has antibacterial activity against Clostridium difficile, enterotoxigenic Escherichia coli O157:H7, norovirus, and other common intestinal pathogens such as Salmonella and Shigella.
Bismuth subsalicylate is widely available over-the-counter as an antidiarrheal and antacid medication, with Pepto-Bismol being the most well-known brand. It is indicated for the treatment of diarrhea, indigestion, nausea, and heartburn. The compound is also used for the prevention of traveler's diarrhea. Bismuth subsalicylate exhibits antibacterial and gastroprotective properties. It reduces inflammation of the stomach and intestinal lining through inhibition of prostaglandin synthesis. The compound works by forming a protective coating on the lining of the stomach and intestines, which helps to reduce irritation and inflammation. Bismuth subsalicylate is available in various formulations, including liquid suspensions, chewable tablets, and caplets. It is generally well-tolerated and is considered safe for short-term use in adults and children over 12 years of age. The compound's dual antisecretory and antimicrobial mechanism of action makes it effective for the treatment of various diarrheal disorders.

C7H6BIO4

363.1005

361.999

14882-18-9

16682734

White to off-white solid powder

336.3ºC at 760mmHg

>35ºC

144.5ºC

4.45E-05mmHg at 25°C

0.974

1

4

0

12

173

0

QBWLKDFBINPHFT-UHFFFAOYSA-L

InChI=1S/C7H6O3.Bi.H2O/c8-6-4-2-1-3-5(6)7(9)10;;/h1-4,8H,(H,9,10);;1H2/q;+2;/p-2

2934.99.9001

Powder      -20°C    3 years

                     4°C     2 years

In solvent   -80°C    6 months

                  -20°C    1 month

Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)

DMSO : ~1 mg/mL (~2.76 mM)
H2O : ~0.1 mg/mL (~0.28 mM)

Note: Listed below are some common formulations that may be used to formulate products with low water solubility (e.g. < 1 mg/mL), you may test these formulations using a minute amount of products to avoid loss of samples.

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Injection Formulation 1: DMSO : Tween 80： Saline = 10 : 5 : 85 (i.e. 100 μL DMSO stock solution → 50 μL Tween 80 → 850 μL Saline)
*Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH ₂ O to obtain a clear solution.
Injection Formulation 2: DMSO : PEG300 ：Tween 80 : Saline = 10 : 40 : 5 : 45 (i.e. 100 μL DMSO → 400 μLPEG300 → 50 μL Tween 80 → 450 μL Saline)
Injection Formulation 3: DMSO : Corn oil = 10 : 90 (i.e. 100 μL DMSO → 900 μL Corn oil)
Example: Take the Injection Formulation 3 (DMSO : Corn oil = 10 : 90) as an example, if 1 mL of 2.5 mg/mL working solution is to be prepared, you can take 100 μL 25 mg/mL DMSO stock solution and add to 900 μL corn oil, mix well to obtain a clear or suspension solution (2.5 mg/mL, ready for use in animals).

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Injection Formulation 4: DMSO : 20% SBE-β-CD in saline = 10 : 90 [i.e. 100 μL DMSO → 900 μL (20% SBE-β-CD in saline)]
*Preparation of 20% SBE-β-CD in Saline (4°C，1 week): Dissolve 2 g SBE-β-CD in 10 mL saline to obtain a clear solution.
Injection Formulation 5: 2-Hydroxypropyl-β-cyclodextrin : Saline = 50 : 50 (i.e. 500 μL 2-Hydroxypropyl-β-cyclodextrin → 500 μL Saline)
Injection Formulation 6: DMSO : PEG300 : castor oil : Saline = 5 : 10 : 20 : 65 (i.e. 50 μL DMSO → 100 μLPEG300 → 200 μL castor oil → 650 μL Saline)
Injection Formulation 7: Ethanol : Cremophor : Saline = 10： 10 : 80 (i.e. 100 μL Ethanol → 100 μL Cremophor → 800 μL Saline)
Injection Formulation 8: Dissolve in Cremophor/Ethanol (50 : 50), then diluted by Saline
Injection Formulation 9: EtOH : Corn oil = 10 : 90 (i.e. 100 μL EtOH → 900 μL Corn oil)
Injection Formulation 10: EtOH : PEG300：Tween 80 : Saline = 10 : 40 : 5 : 45 (i.e. 100 μL EtOH → 400 μLPEG300 → 50 μL Tween 80 → 450 μL Saline)

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Oral Formulation 1: Suspend in 0.5% CMC Na (carboxymethylcellulose sodium)
Oral Formulation 2: Suspend in 0.5% Carboxymethyl cellulose
Example: Take the Oral Formulation 1 (Suspend in 0.5% CMC Na) as an example, if 100 mL of 2.5 mg/mL working solution is to be prepared, you can first prepare 0.5% CMC Na solution by measuring 0.5 g CMC Na and dissolve it in 100 mL ddH2O to obtain a clear solution; then add 250 mg of the product to 100 mL 0.5% CMC Na solution, to make the suspension solution (2.5 mg/mL, ready for use in animals).

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Oral Formulation 3: Dissolved in PEG400
Oral Formulation 4: Suspend in 0.2% Carboxymethyl cellulose
Oral Formulation 5: Dissolve in 0.25% Tween 80 and 0.5% Carboxymethyl cellulose
Oral Formulation 6: Mixing with food powders

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Note: Please be aware that the above formulations are for reference only. InvivoChem strongly recommends customers to read literature methods/protocols carefully before determining which formulation you should use for in vivo studies, as different compounds have different solubility properties and have to be formulated differently.

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 (Please use freshly prepared in vivo formulations for optimal results.)