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 hydrolyzes into bismuth and salicylic acid in the stomach. Salicylic acid is almost completely absorbed in the small intestine and reaches plasma peak levels one to two hours after dosing. In one study involving healthy male subjects, oral administration of 60 mL Pepto-Bismol, a common over-the-counter product of bismuth subsalicylate, equivalent to 1050 mg of bismuth subsalicylate, resulted in the peak plasma concentration of salicylate of 40.1 μg/mL, with a time to peak concentration (Tmax) of 1.8 hours. Less than 1% of bismuth from bismuth subsalicylate is absorbed from the gastrointestinal tract into the systemic circulation. In one study, oral administration of 787 mg bismuth subsalicylate in the chewable tablet form for two weeks resulted in the mean trough blood bismuth concentration was 5.1 ± 3.1 ng/mL. In another study, the mean trough blood bismuth concentration ranged from five to 32 ng/mL following oral administration of 525 mg bismuth subsalicylate in the liquid suspension form.
Following oral administration, salicylate dissociated from bismuth subsalicylate is excreted in the urine. Bismuth is primarily eliminated via urinary and biliary routes.
There is no information available.
The renal clearance of bismuth is 50 ± 18 mL/min.
THE AUTOPSY DISTRIBUTION OF BISMUTH IN 22 PATIENTS WHO RECEIVED THERAPEUTIC IM INJECTIONS (MAINLY BISMUTH SALICYLATE) WAS AS FOLLOWS (MEDIAN VALUES, 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 subsalicylate is converted to salicylic acid and insoluble bismuth salts. The salicylate portion of bismuth subsalicylate is extensively absorbed (greater than 90%) and excreted in urine.
Bismuth subsalicylate (bismuth salicylate) is hydrolyzed in the gastrointestinal tract to bismuth salts and sodium salicylate. Two tablets or 30 ml suspension of the compound yields 204 mg and 258 mg, respectively, of salicylate. Inorganic bismuth salts, in contrast to organic complexes of bismuth, are relatively water-insoluble and poorly absorbed systemically, but significant absorption of salicylate does occur. A brief 1992 study found minimal absorption of bismuth (exact serum concentrations not specified) from bismuth subsalicylate in 12 healthy subjects, as opposed to a peak serum level of 0.050 ug/ml after a dose of 216 mg of colloidal bismuth subcitrate in a single patient. Some bismuth absorption was documented across the normal gastric mucosa, but the primary absorption occurred from the duodenum.

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Metabolism / Metabolites
Bismuth subsalicylate undergo hydrolysis at pH levels lesser than three. It is largely hydrolyzed in the stomach to bismuth oxychloride and salicylic acid. In the small intestine, unchanged bismuth subsalicylate reacts with other anions such as bicarbonate and phosphate to form insoluble bismuth salts. In the colon, unchanged bismuth subsalicylate and other bismuth salts react with hydrogen sulfide produced by anaerobic bacteria to form bismuth sulfide, a highly insoluble black salt responsible for the darkening of the stools.

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Biological Half-Life
The terminal half-life of salicylic acid following a single oral dose of 525 mg bismuth subsalicylate is ranges from two to five hours. Bismuth has an intermediate half-life of 5 to 11 days and a terminal half-life of 21 to 72 days.

Effects During Pregnancy and Lactation
◉ Summary of Use during Lactation
Because of the possibility of absorption of salicylate from the breastmilk by the infant, alternate therapies are preferred.
◉ Effects in Breastfed Infants
One case report of metabolic acidosis was caused by salicylate in a 16-day old breastfed infant whose mother was taking aspirin 650 mg every 4 hours for arthritis. However, there was no measurement of salicylate in maternal serum or milk and it is unclear whether the infant had received any salicylate directly.
◉ Effects on Lactation and Breastmilk
Relevant published information was not found as of the revision date.

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Protein Binding
Salicylic acid is about 90% plasma protein bound. Bismuth is about >90% bound to plasma proteins.

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Interactions
BIOAVAILABILITY OF DOXYCYCLINE WAS SIGNIFICANTLY REDUCED BY 37% & 51%, RESPECTIVELY, WHEN SUBSALICYLATE BISMUTH WAS GIVEN SIMULTANEOUSLY & AS A MULTIPLE-DOSE REGIMEN BEFORE DOXYCYCLINE. SUBSALICYLATE BISMUTH 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 MEDICINALLY AS INTESTINAL ABSORBENT.
MEDICATION (VET): ANTIDIARRHEAL. WEAK INTESTINAL ANTISEPTIC DUE TO LIBERATION OF SALICYLIC ACID. USUALLY COMBINED WITH CARBONATES TO MINIMIZE IRRITANT EFFECTS OF FREE ACID WHILE UTILIZING PROTECTIVE EFFECT OF BISMUTH.
THE CMPD IS SOMETIMES USED ORALLY TO ALLAY DIARRHEA OR TO SOOTHE GASTRITIS OR PEPTIC ULCER. ... BEFORE THE ADVENT OF PENICILLIN, BISMUTH SUBSALICYLATE WAS MUCH USED IN THE TREATMENT OF SYPHILIS...
/SRP: FORMER/ TREATMENT OF VINCENT'S ANGINA, SYPHILIS
For more Therapeutic Uses (Complete) data for BISMUTH SUBSALICYLATE (7 total), please visit the HSDB record page.

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Drug Warnings
EVEN WHEN ITS USE WAS EXTENSIVE, THE GRADUAL IM INJECTION USED AGAINST SYPHILIS RARELY LED TO SERIOUS POISONING. IT WAS CUSTOMARY TO STOP TREATMENT IF GINGIVITIS, ALBUMINURIA, CUTANEOUS ERUPTIONS, OR MARKED DIARRHEA APPEARED.
BIOAVAILABILITY OF DOXYCYCLINE WAS SIGNIFICANTLY REDUCED BY 37% & 51%, RESPECTIVELY, WHEN SUBSALICYLATE BISMUTH WAS GIVEN SIMULTANEOUSLY & AS A MULTIPLE-DOSE REGIMEN BEFORE DOXYCYCLINE. SUBSALICYLATE BISMUTH SHOULD NOT BE TAKEN WHEN DOXYCYCLINE IS USED FOR THERAPEUTIC PURPOSES. AUTHORS SUGGEST TRAVELERS SHOULD NOT TAKE THE AGENTS TOGETHER IN AN EFFORT TO PREVENT DIARRHEA.
The excretion of large amounts of bismuth obtained from bismuth subsalicylate into breast milk is not expected because of the poor absorption of bismuth into the systemic circulation. Salicylates, however, are excreted in milk and are eliminated more slowly from milk than from plasma with milk:plasma ratios, rising from 0.03-0.08 at 3 hours to 0.34 at 12 hours. Due to the potential for adverse effects in the nursing infant, the American Academy of Pediatrics recommends that salicylates should be used cautiously during breast feeding. A recent review also states that bismuth subsalicylate should be avoided during lactation because of systemic salicylate absorption.
Although the risk for toxicity may be small, significant fetal adverse effects have resulted from chronic exposure to salicylates Because of this, the use of bismuth subsalicyate during gestation should be restricted to the first half of pregnancy and then only in amounts that do not exceed the recommended doses.

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Pharmacodynamics
Bismuth subsalicylate is an antacid and antimicrobial, gastroprotective, anti-secretory, and anti-inflammatory actions. It works to reduce the severity and incidence of flatulence and diarrhea, and consequently relieving gastrointestinal discomfort. In one study, bismuth subsalicylate was prevented traveler's diarrhea with a protection rate >60%. Organobismuth compounds, formed by the breakdown of bismuth subsalicylate in the gastrointestinal tract, inhibit the growth of _Helicobacter pylori_ and other bacteria implicated in gastrointestinal disorders, and some fungi. In one study, bismuth subsalicylate was shown to eradicate up to 90% of _H. pylori_ infection when used as part of a quadruple therapy regimen containing a proton pump inhibitor, tetracycline, and metronidazole. Bismuth subsalicylate exhibited antimicrobial activity against _Clostridium difficile_, enterotoxigenic _Escherichia coli_ O157:H7, _norovirus_, and other common enteric 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.)