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].

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.

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.

[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.

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.)