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| Clinical data | |
|---|---|
| Other names | vitamin B12, vitamin B12a, hydroxycobalamin |
| AHFS/Drugs.com | Monograph |
| MedlinePlus | a605007 |
| Routes of administration | Oral,Intramuscular,intravenous |
| ATC code | |
| Legal status | |
| Legal status | |
| Pharmacokinetic data | |
| Protein binding | Very high (90%) |
| Metabolism | Primarily liver, cobalamins are absorbed in the ileum and stored in the liver. |
| Eliminationhalf-life | ~6 days |
| Identifiers | |
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| CAS Number | |
| PubChemCID | |
| DrugBank | |
| ChemSpider | |
| UNII | |
| KEGG | |
| ChEBI | |
| ChEMBL | |
| CompTox Dashboard(EPA) | |
| ECHA InfoCard | 100.033.198 |
| Chemical and physical data | |
| Formula | C62H89CoN13O15P |
| Molar mass | 1346.377 g·mol−1 |
| 3D model (JSmol) | |
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Hydroxocobalamin, also known asvitamin B12a andhydroxycobalamin, is avitamin found in food and used as adietary supplement.[1] As a supplement it is used to treatvitamin B12 deficiency includingpernicious anemia.[1][2] Other uses include treatment forcyanide poisoning,Leber's optic atrophy, andtoxic amblyopia.[3][4] It is given byinjection into a muscle orvein,[2] by pill or sublingually.
Side effects are generally few.[2] They may includediarrhea,feeling sick, hot flushes, itchiness,low blood potassium,allergic reactions, andhigh blood pressure.[2] Normal doses are considered safe inpregnancy.[5] No overdosage or toxicity has been reported with this drug.[2] Hydroxocobalamin is the natural form ofvitamin B12 and a member of thecobalamin family of compounds.[6][7] It is found in both raw and cooked beef, together with other cobalamins.[8] Hydroxocobalamin, or another form of vitamin B12, are required for the body to makeDNA.[7]
Hydroxocobalamin was first isolated in 1949.[9] It is on theWorld Health Organization's List of Essential Medicines.[10] Hydroxocobalamin is available as ageneric medication.[2] Commercially it is made using one of a number of types ofbacteria.[11]
Standard therapy for treatment of vitamin B12 deficiency has been intramuscular (IM) or intravenous (IV) injections of hydroxocobalamin (OHCbl), since the majority of cases are due to malabsorption by the enteral route (gut).[12] It is used inpediatric patients with intrinsic cobalaminmetabolic diseases, vitamin B12-deficient patients with tobacco amblyopia due to cyanide poisoning, and patients with pernicious anemia who have optic neuropathy.[13]
In a newly diagnosed vitamin B12-deficient patient, normally defined as when serum levels are less than 200 pg/ml, daily IM injections of hydroxocobalamin up to 1,000 μg (1 mg) per day are given to replenish the body's depleted cobalamin stores. In the presence of neurological symptoms, following daily treatment, injections up to weekly or biweekly are indicated for six months before initiating monthly IM injections. Once clinical improvement is confirmed, maintenance supplementation of B12 will generally be needed for life.[citation needed]
Although less common in this form than cyanocobalamine and methylcobalamine, hydroxocobalamine is also available as pills for oral orsublingual administration. However, one study on the treatment of children withmethylmalonic acidemia andhomocystinuria found oral hydroxocobalamine at 1 mg daily to be ineffective in reducing levels ofhomocysteine. In a trial on adult volunteers, this dose did not lead to a significant increase in serum vitamin B12 levels when given thrice daily for one week. In addition, once-daily administration of 1 mg oral hydroxocobalamine caused the studied children's levels of homocysteine to increase and their levels ofmethionine to decrease, while the reverse happened when hydroxocobalamine was given intramuscularly.[14]
In 2006 theFDA approved hydroxocobalamin for treating smoke inhalation, which can cause cyanide poisoning.[15] Hydroxocobalamin is first line therapy for people withcyanide poisoning.[2] Hydroxocobalamin converts cyanide to the much less toxiccyanocobalamin. Cyanocobalamin is renally cleared. The use of hydroxocobalamin became first line due to its low adverse risk profile, rapid onset of action, and ease of use in the prehospital setting.[16]
Injection of hydroxocobalamin is used to rectify the following causes of vitamin B12 deficiency (list taken from the drug prescription label published by theU.S. Food and Drug Administration)
Pernicious anemia is the most common cause of vitamin B12 deficiency.[17] While it technically refers to anemia caused specifically by autoimmune deficiency of intrinsic factor, it is commonly used to refer to B12-deficient anemia as a whole, regardless of cause.
The literature data on the acute toxicity profile of hydroxocobalamin show it is generally regarded as safe with local and systemic exposure. The ability of hydroxocobalamin to rapidly scavenge and detoxify cyanide by chelation has resulted in several acute animal and human studies using systemic hydroxocobalamin doses at suprapharmacological doses as high as 140 mg/kg to support its use as anintravenous (IV) treatment for cyanide exposure.[18][19] The US FDA at the end of 2006 approved the use hydroxocobalamin as an injection for the treatment of cyanide poisoning.
The drug causes a reddish discoloration of the urine (chromaturia, which can look likeblood in the urine), and of the skin.[20][21] It also causes self-limiting hypertension, however due to the hypotension affects of cyanide and carbon monoxide poisoning, it is not bad.[22]
Hydroxocobalamin acetate occurs as odorless, dark-redorthorhombic crystals. The injection formulations appear as clear, dark-red solutions. It has adistribution coefficient of1.133×10^−5 and apKa of 7.65.[citation needed]
Vitamin B12 refers to a group of compounds called cobalamins that are available in the human body in a variety of mostly interconvertible forms. Together withfolate, cobalamins are essential cofactors required forDNA synthesis in cells wherechromosomal replication and division are occurring—most notably thebone marrow andmyeloid cells. As acofactor, cobalamins are essential for two cellular reactions:
Cobalamins are characterized by aporphyrin-likecorrin nucleus that contains a singlecobalt atom bound to abenzimidazolylnucleotide and a variable residue (R) group. The variable R group gives rise to the four most commonly known cobalamins:cyanocobalamin (CNCbl),methylcobalamin (MeCbl),adenosylcobalamin (AdCbl, also known as cobamamide or 5-deoxyadenosylcobalamin), and hydroxocobalamin (OHCbl). In the serum, hydroxocobalamin and cyanocobalamin are believed to function as storage or transport forms of the molecule, whereas methylcobalamin and adenosylcobalamin are the active forms of the coenzyme required for cell growth and replication.[23] Cyanocobalamin is usually converted to hydroxocobalamin in the serum, whereas hydroxocobalamin is converted to either methylcobalamin or adenosylcobalamin. Cobalamins circulate bound to serum proteins calledtranscobalamins (TC) andhaptocorrins. Hydroxocobalamin has a higher affinity to the TC II transport protein than cyanocobalamin, or adenosylcobalamin. From abiochemical point of view, two essential enzymatic reactions require vitamin B12 (cobalamin).[23][24]
Intracellular vitamin B12 is maintained in two active coenzymes, methylcobalamin and adenosylcobalamin. In the face of vitamin B12 deficiency, conversion of methylmalonyl-CoA tosuccinyl-CoA cannot take place, which results in accumulation of methylmalonyl-CoA and aberrant fatty acid synthesis. In the other enzymatic reaction, methylcobalamin supports the methionine synthase reaction, which is essential for normal metabolism of folate. The folate-cobalamin interaction is pivotal for normal synthesis ofpurines andpyrimidines and the transfer of the methyl group to cobalamin is essential for the adequate supply oftetrahydrofolate, the substrate for metabolic steps that require folate. In a state of vitamin B12 deficiency, the cell responds by redirecting folate metabolic pathways to supply increasing amounts ofmethyltetrahydrofolate. The resulting elevated concentrations ofhomocysteine andMMA are often found in patients with low serum vitamin B12 and can usually be lowered with successful vitamin B12 replacement therapy. However, elevatedMMA andhomocysteine concentrations may persist in patients with cobalamin concentrations between 200 and 350 pg/mL.[25] Supplementation with vitamin B12 during conditions of deficiency restores the intracellular level of cobalamin and maintains a sufficient level of the two active coenzymes: methylcobalamin and adenosylcobalamin.
