Vitamin B12

Absorption

Vitamin B12 is quickly absorbed from intramuscular (IM) and subcutaneous (SC) sites of injection; with peak plasma concentrations achieved about 1 hour after IM injection .
Orally administered vitamin B12 binds to intrinsic factor (IF) during its transport through the stomach. The separation of Vitamin B12 and IF occurs in the terminal ileum when calcium is present, and vitamin B12 is then absorbed into the gastrointestinal mucosal cells. It is then transported by transcobalamin binding proteins . Passive diffusion through the intestinal wall can occur, however, high doses of vitamin B12 are required in this case (i.e. >1 mg). After the administration of oral doses less than 3 mcg, peak plasma concentrations are not reached for 8 to 12 hours, because the vitamin is temporarily retained in the wall of the lower ileum .

Toxicity

LD50 Oral (mouse): > 5,000 mg/kg .
General toxicity
Vitamin B12 is generally non-toxic, even at higher doses. Mild, transient diarrhea, polycythemia vera, peripheral vascular thrombosis, itching, transitory exanthema, a feeling of swelling of entire body, pulmonary edema and congestive heart failure in early treatment stages, anaphylactic shock and death have been observed after vitamin B12 administration .
Carcinogenesis and mutagenesis
Long term studies in animals examining the carcinogenic potential of any of the vitamin B12 formulations have not completed to date. There is no evidence from long-term use in patients with pernicious anemia that vitamin B12 has carcinogenic potential. Pernicious anemia is known to be associated with an increased incidence of stomach carcinoma, however, this malignancy has been attributed to the underlying cause of pernicious anemia and has not been found to be related to treatment with vitamin B12 .
Use in pregnancy
No adverse effects have been reported with ingestion of normal daily requirements during pregnancy .
A note on the use of the nasal spray in pregnancy
Although vitamin B12 is an essential vitamin and requirements are increased during pregnancy, it is currently unknown whether the nasal spray form can cause fetal harm when administered to a pregnant woman or can affect reproduction capacity. The nasal spray form should be given to a pregnant woman only if clearly needed, as it is considered a pregnancy category C drug in this form. Sufficient well-controlled studies have not been done to this date in pregnant women .
Use in lactation
Vitamin B12 has been found distributed into the milk of nursing women in concentrations similar to the maternal blood vitamin B12 concentrations. No adverse effects have been reported to date with intake of normal required doses during lactation .

Description

Vitamin B12 contains a cobalt atom, a rarity in natural products. The basic vitamin B12 structure has several chemical forms that differ by the substituent on the central cobalt atom. It is a manufactured form of the vitamin made from natural forms and used in supplements because it is highly bioavailable. Vitamin B12 has an extensive history. Hodgkin received the 1964 Nobel Prize in Chemistry for her structure studies on vitamin B12 and other complex molecules. Woodward and Eschenmoser had been awarded earlier Nobels for their achievements in natural product synthesis. Vitamin B12 is found in every cell in the body and has multiple functions, including acting as a cofactor in DNA synthesis. Animal-based foods (meat, milk, and eggs) are the primary sources. Hence, vegetarians, especially vegans, must include plant- or bacterium-derived vitamin B12 supplements in their diets.

The Uses of Vitamin B12

Prototype of the family of naturally occurring cobalt coordination compounds knows as corrinoids. Analogs of vitamin B12 which differ only in the β-ligand of the cobalt are termed cobalamins. Synthesi zed almost exclusively by bacteria. Dietary sources include fish, meat, liver, and dairy products; plants have little or no cobalamins. Converted by the body into its bioactive forms, methylcobalamin and cobamamide, which serve as enzyme cofactors. Severe deficiency may result in megaloblastic anemia and/or neurological impairment.

Indications

Nasal spray
The cyanocobalamin nasal spray is indicated for the maintenance of vitamin B12 concentrations after normalization with intramuscular vitamin B12 therapy in patients with deficiency of this vitamin who have no nervous system involvement .
Note: CaloMist , the nasal spray form, has not been evaluated for the treatment of newly diagnosed vitamin B12 deficiency.
Injection forms (subcutaneous, intramuscular)
These forms are indicated for vitamin B12 deficiencies due to various causes, with or without neurologic manifestations . Vitamin B12 deficiency is frequently caused by malabsorption, which is often associated with the following conditions :
Addisonian (pernicious) anemia
Gastrointestinal pathology, dysfunction, or surgery, including gluten enteropathy or sprue, small bowel bacterial overgrowth, total or partial gastrectomy
Fish tapeworm infestation
Malignancy of the pancreas or bowel
Folic acid deficiency
Oral forms
Vitamin B12 supplements are widely available and indicated in patients who require supplementation for various reasons. Dose requirements for vitamin B12 which are higher than normal (caused by pregnancy, thyrotoxicosis, hemolytic anemia, hemorrhage, malignancy, hepatic and renal disease) can usually be achieved with oral supplementation . Oral products of vitamin B12 are not recommended in patients with malabsorption, as these forms are primarily absorbed in the gastrointestinal tract .

Background

Cyanocobalamin (commonly known as Vitamin B12) is a highly complex, essential vitamin, owing its name to the fact that it contains the mineral, cobalt. This vitamin is produced naturally by bacteria , and is necessary for DNA synthesis and cellular energy production. Vitamin B12 has many forms, including the cyano-, methyl-, deoxyadenosyl- and hydroxy-cobalamin forms. The cyano form, is the most widely used form in supplements and prescription drugs , . Several pharmaceutical forms of cyanocobalamin have been developed, including the tablet, injection, and nasal spray forms , , . This drug was initially approved by the FDA in 1942 .

Biological Functions

Cyanocobalamin corrects vitamin B12 deficiency and improves the symptoms and laboratory abnormalities associated with pernicious anemia (megaloblastic indices, gastrointestinal lesions, and neurologic damage). This drug aids growth, cell reproduction, hematopoiesis, nucleoprotein, and myelin synthesis. It also plays a vital role in fat metabolism, carbohydrate metabolism, and protein synthesis. Cells that undergo rapid division (for example, epithelial cells, bone marrow, and myeloid cells) have a high demand for vitamin B12.

Metabolism

Vitamin B12 or cyanocobalamin obtained from food is initially bound by haptocorrin, a protein found in the saliva with high affinity for B12. This forms a haptocorrin-B12 complex. Cyanocobalamin passes through the stomach and is protected from acid degradation due to its binding to haptocorrin. In the duodenum, pancreatic proteases release cobalamin from the haptocorrin-B12 complex and from other proteins containing protein-bound B12 that have been ingested. Following this, the binding of cobalamin to a second glycoprotein, intrinsic factor, promotes its uptake by terminal ileum mucosal cells by a process called cubilin/AMN receptor-mediated endocytosis. After absorption into enterocytes, intrinsic factor is broken down in the lysosome, and cobalamin is then released into the bloodstream. The transporter ABCC1, found in the basolateral membrane of intestinal epithelial and other cells, exports cobalamin bound to transcobalamin out of the cell . Cyanocobalamin then passes through the portal vein in the liver, and then reaches the systemic circulation. The active forms of cyanocobalamin are methylcobalamin and adenosylcobalamin , .