Clinical data | |
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Pronunciation | sye AN oh koe BAL a min [2] |
Trade names | Cobolin-M, [2] Depo-Cobolin, [2] others [3] |
AHFS/ Drugs.com | Professional Drug Facts |
MedlinePlus | a604029 |
License data | |
Pregnancy category |
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Routes of administration | By mouth, intramuscular, nasal spray [5] [6] |
ATC code | |
Legal status | |
Legal status |
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Identifiers | |
CAS Number | |
PubChem CID | |
DrugBank | |
ChemSpider | |
UNII | |
KEGG | |
ChEMBL | |
ECHA InfoCard | 100.000.618 |
Chemical and physical data | |
Formula | C63H88CoN14O14P |
Molar mass | 1355.388 g·mol−1 |
3D model ( JSmol) | |
Melting point | 300 °C (572 °F) + |
Boiling point | 300 °C (572 °F) + |
Solubility in water | 1/80g/ml |
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Cyanocobalamin is a form of
vitamin B
12 used to treat and prevent
vitamin B
12 deficiency except in the presence of cyanide toxicity.
[7]
[8]
[2] The deficiency may occur in
pernicious anemia, following
surgical removal of the stomach, with
fish tapeworm, or due to
bowel cancer.
[9]
[5] It is used by mouth, by
injection into a muscle, or as a
nasal spray.
[5]
[6]
Cyanocobalamin is generally well tolerated.
[10] Minor side effects may include diarrhea, nausea, upset stomach, and itchiness.
[11] Serious side effects may include
anaphylaxis, and
low blood potassium resulting in
heart failure.
[11] Use is not recommended in those who are allergic to
cobalt or have
Leber's disease.
[9] No overdosage or toxicity has been reported.
[11] It is less preferred than
hydroxocobalamin for treating vitamin B
12 deficiency because it has slightly lower bioavailability. Some study have shown that it has an antihypotensive effect.
[5] Vitamin B
12 is an
essential nutrient meaning that it cannot be made by the body but is required for life.
[12]
[10]
Cyanocobalamin was first manufactured in the 1940s. [13] It is available as a generic medication and over the counter. [5] [10] In 2021, it was the 110th most commonly prescribed medication in the United States, with more than 5 million prescriptions. [14] [15]
Cyanocobalamin is usually prescribed after surgical removal of part or all of the
stomach or
intestine to ensure adequate serum levels of vitamin B
12. It is also used to treat
pernicious anemia,
vitamin B
12 deficiency (due to low intake from food or inability to absorb due to genetic or other factors),
thyrotoxicosis,
hemorrhage,
malignancy, liver disease and kidney disease. Cyanocobalamin injections are often prescribed to
gastric bypass patients who have had part of their
small intestine bypassed, making it difficult for B
12 to be acquired via food or vitamins. Cyanocobalamin is also used to perform the
Schilling test to check ability to absorb vitamin B
12.
[16]
Cyanocobalamin is also produced in the body (and then excreted via urine) after intravenous hydroxycobalamin is used to treat cyanide poisoning. [17]
Possible side effects of cyanocobalamin injection include allergic reactions such as hives, difficult breathing; redness of the face; swelling of the arms, hands, feet, ankles or lower legs; extreme thirst; and diarrhea. Less-serious side effects may include headache, dizziness, leg pain, itching, or rash. [18]
Treatment of
megaloblastic anemia with concurrent vitamin B
12 deficiency using B
12 vitamers (including cyanocobalamin), creates the possibility of
hypokalemia due to increased
erythropoiesis (red blood cell production) and consequent cellular uptake of
potassium upon anemia resolution.
[19] When treated with cyanocobalamin, patients with
Leber's disease may develop serious
optic atrophy, possibly leading to blindness.
[20]
Vitamin B
12 is the "generic descriptor" name for any
vitamers of vitamin B
12. Animals, including humans, can convert cyanocobalamin to any one of the active vitamin B
12 compounds.
[21]
Cyanocobalamin is one of the most widely manufactured
vitamers in the vitamin B
12 family (the family of chemicals that function as B
12 when put into the body), because cyanocobalamin is the most air-stable of the B
12 forms.
[22] It is the easiest
[23] to crystallize and therefore easiest
[24] to purify after it is produced by
bacterial fermentation. It can be obtained as dark red crystals or as an amorphous red powder. Cyanocobalamin is
hygroscopic in the
anhydrous form, and sparingly soluble in water (1:80).
[25] It is stable to
autoclaving for short periods at 121 °C (250 °F). The vitamin B
12
coenzymes are unstable in light. After consumption the cyanide
ligand is replaced by other groups (
adenosyl,
methyl) to produce the biologically active forms. The
cyanide is converted to
thiocyanate and excreted by the kidney.
[26]
In the cobalamins,
cobalt normally exists in the trivalent state, Co(III). However, under reducing conditions, the cobalt center is reduced to Co(II) or even Co(I), which are usually denoted as B
12r and B
12s, for reduced and super reduced, respectively.
B
12r and B
12s can be prepared from cyanocobalamin by controlled potential reduction, or chemical reduction using
sodium borohydride in alkaline solution,
zinc in
acetic acid, or by the action of
thiols. Both B
12r and B
12s are stable indefinitely under oxygen-free conditions. B
12r appears orange-brown in solution, while B
12s appears bluish-green under natural daylight, and purple under artificial light.
[27]
B
12s is one of the most nucleophilic species known in aqueous solution.
[27] This property allows the convenient preparation of cobalamin analogs with different
substituents, via
nucleophilic attack on
alkyl halides and vinyl halides.
[27]
For example, cyanocobalamin can be converted to its analog cobalamins via reduction to B
12s, followed by the addition of the corresponding
alkyl halides,
acyl halides,
alkene or
alkyne.
Steric hindrance is the major limiting factor in the synthesis of the B
12 coenzyme analogs. For example, no reaction occurs between
neopentyl chloride and B
12s, whereas the secondary alkyl halide analogs are too unstable to be isolated.
[27] This effect may be due to the strong coordination between
benzimidazole and the central cobalt atom, pulling it down into the plane of the
corrin ring. The
trans effect determines the polarizability of the Co–C bond so formed. However, once the
benzimidazole is detached from cobalt by quaternization with
methyl iodide, it is replaced by H
2O or
hydroxyl ions. Various secondary alkyl halides are then readily attacked by the modified B
12s to give the corresponding stable cobalamin analogs.
[28] The products are usually extracted and purified by phenol-methylene chloride extraction or by column chromatography.
[27]
Cobalamin analogs prepared by this method include the naturally occurring coenzymes methylcobalamin and cobamamide, and other cobalamins that do not occur naturally, such as vinylcobalamin, carboxymethylcobalamin and cyclohexylcobalamin. [27] This reaction is under review for use as a catalyst for chemical dehalogenation, organic reagent and photosensitized catalyst systems. [29]
Cyanocobalamin is commercially prepared by
bacterial fermentation. Fermentation by a variety of
microorganisms yields a mixture of
methylcobalamin,
hydroxocobalamin and
adenosylcobalamin. These compounds are converted to cyanocobalamin by addition of
potassium cyanide in the presence of
sodium nitrite and heat. Since multiple species of
Propionibacterium produce no
exotoxins or
endotoxins and have been granted
GRAS status (generally regarded as safe) by the
United States Food and Drug Administration, they are the preferred bacterial fermentation organisms for vitamin B
12 production.
[30]
Historically, the physiological form was initially thought to be cyanocobalamin. This was because hydroxocobalamin produced by bacteria was changed to cyanocobalamin during purification in activated charcoal columns after separation from the bacterial cultures (because cyanide is naturally present in activated charcoal). [31] Cyanocobalamin is the form in most pharmaceutical preparations because adding cyanide stabilizes the molecule. [32]
The total world production of vitamin B12, by four companies (the French Sanofi-Aventis and three Chinese companies) in 2008 was 35 tonnes. [33]
The two bioactive forms of vitamin B
12 are
methylcobalamin in
cytosol and
adenosylcobalamin in
mitochondria. Multivitamins often contain cyanocobalamin, which is presumably converted to bioactive forms in the body. Both methylcobalamin and adenosylcobalamin are commercially available as supplement pills. The
MMACHC gene product catalyzes the decyanation of cyanocobalamin as well as the dealkylation of alkylcobalamins including methylcobalamin and adenosylcobalamin.
[34] This function has also been attributed to
cobalamin reductases.
[35] The MMACHC gene product and cobalamin reductases enable the interconversion of cyano- and alkylcobalamins.
[36]
Cyanocobalamin is added to fortify
[37] nutrition, including baby milk powder, breakfast cereals and
energy drinks for humans, also animal feed for poultry, swine and fish. Vitamin B
12 becomes inactive due to
hydrogen cyanide and
nitric oxide in cigarette smoke. Vitamin B
12 also becomes inactive due to
nitrous oxide N
2O commonly known as laughing gas, used for
anaesthesia and as a recreational drug.
[38] Vitamin B
12 becomes inactive due to microwaving or other forms of heating.
[39]
Methylcobalamin and 5-methyltetrahydrofolate are needed by methionine synthase in the methionine cycle to transfer a methyl group from 5-methyltetrahydrofolate to homocysteine, thereby generating tetrahydrofolate (THF) and methionine, which is used to make SAMe. SAMe is the universal methyl donor and is used for DNA methylation and to make phospholipid membranes, choline, sphingomyelin, acetylcholine, and other neurotransmitters.
The enzymes that use B
12 as a built-in cofactor are
methylmalonyl-CoA mutase (
PDB 4REQ
[40]) and
methionine synthase (
PDB 1Q8J).
[41]
The metabolism of
propionyl-CoA occurs in the mitochondria and requires Vitamin B
12 (as
adenosylcobalamin) to make
succinyl-CoA. When the conversion of propionyl-CoA to succinyl-CoA in the mitochondria fails due to Vitamin B
12 deficiency, elevated blood levels of
methylmalonic acid (MMA) occur. Thus, elevated blood levels of
homocysteine and MMA may both be indicators of
vitamin B
12 deficiency.
Adenosylcobalamin is needed as
cofactor in
methylmalonyl-CoA mutase—MUT enzyme. Processing of cholesterol and protein gives
propionyl-CoA that is converted to
methylmalonyl-CoA, which is used by
MUT enzyme to make
succinyl-CoA. Vitamin B
12 is needed to prevent anemia, since making
porphyrin and
heme in
mitochondria for producing hemoglobin in red blood cells depends on
succinyl-CoA made by vitamin B
12.
Inadequate absorption of vitamin B
12 may be related to
coeliac disease. Intestinal absorption of vitamin B
12 requires successively three different protein molecules:
haptocorrin,
intrinsic factor and
transcobalamin II.