Hydroxocobalamin

Hydroxocobalamin
Systematic (IUPAC) name
Coα-[α-(5,6-dimethylbenzimidazolyl)]-
Coβ-hydroxocobamide
Clinical data
AHFS/Drugs.com Consumer Drug Information
MedlinePlus a605007
Pregnancy
category
Routes of
administration		 Injectable (intramuscular, intravenous, or subcutaneous)
Legal status
Legal status
  • US: OTC
  • Prescription injectable in U.S. Not DEA-controlled
Pharmacokinetic data
Protein binding Very high (90%)
Metabolism Primarily hepatic, cobalamins are absorbed in the ileum and stored in the liver.
Biological half-life ~6 days
Identifiers
CAS Number 13422-51-0 YesY
ATC code B03BA03 (WHO) V03AB33 (WHO)
PubChem CID 6433575
DrugBank DB00200 YesY
ChemSpider 21160115 YesY
UNII Q40X8H422O YesY
KEGG D01027 YesY
ChEMBL [2] CHEMBL1237097[3] N
Chemical data
Formula C62H89CoN13O15P
Molar mass 1346.37 g/mol
 NYesY (what is this?)  (verify)
Hydroxocobalamin at standard conditions is a solid composed of extremely dark red crystals.
Hydroxocobalamin injection USP (1000 mcg/mL) is a clear red liquid solution of hydoxocobalamin which is available in a 30 mL brown glass multidose vial packaged in a paper box. Shown is 500 mcg B-12 (as 1/2 cc) drawn up in a 1/2 cc U-100 27 gauge x 1/2" insulin syringe, as prepared for subcutaneous injection.

Hydroxocobalamin (also hydroxycobalamin, OHCbl, or B12a) is a natural form, or vitamer, of vitamin B12. It is a member of the cobalamin family of compounds. Hydroxocobalamin is produced by many bacteria that are used to produce the vitamin commercially. Like other forms of vitamin B12, hydroxocobalamin has an intense red color. In humans, it is rapidly converted to usable coenzyme forms of vitamin B12. Hydroxocobalamin is used as an injectable solution for treatment of the vitamin deficiency and for treatment for cyanide poisoning.[4] It has been tested as a scavenger of nitric oxide.

"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 with folate, cobalamins are essential cofactors required for DNA synthesis in cells where chromosomal replication and division are occurring—most notably the bone marrow and myeloid cells. As a cofactor, cobalamins are essential for two cellular reactions:

It is on the WHO Model List of Essential Medicines, the most important medications needed in a basic health system.[5]

Medical uses

Vitamin B12 deficiency

Vitamin B12 compounds are used as a prescription medicine (injection) for vitamin B12 replacement therapy, usually at 100 µg/dose. In the UK, 1,000 µg (1 mg) per dose is generally used. Damage that results from vitamin B12 deficiency can be prevented with early diagnosis and adequate treatment.

For most, the standard therapy for treatment of vitamin B12 deficiency has been intramuscular (IM) injections in the form of cyanocobalamin (CNCbl) or hydroxocobalamin (OHCbl). Cyanocobalamin is traditionally prescribed in the United States. Outside of the United States, hydroxocobalamin is most generally used for vitamin B12 replacement therapy and is considered the “drug of choice” for vitamin B12 deficiency by the Martindale Extra Pharmacopoeia (Sweetman, 2002) and the World Health Organization (WHO) Model List of Essential Drugs. This preference for hydroxocobalamin in many countries is due to its long retention in the body and the need for less-frequent IM injections in restoring vitamin B12 (cobalamin) serum levels. Furthermore, IM administration of hydroxocobalamin is also the preferred treatment for pediatric patients with intrinsic cobalamin metabolic diseases; vitamin B12-deficient patients with tobacco amblyopia due to cyanide poisoning; and patients with pernicious anemia who have optic neuropathy.[6][7][8][9]

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.

Cyanide poisoning

Hydroxocobalamin has also been used in the treatment of cyanide poisoning. Cyanide displaces the hydroxo ligand forming a stable cyanocobalamin.[10]

Toxicity

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 an intravenous (IV) treatment for cyanide exposure.[11][12] The US FDA at the end of 2006 approved the use hydroxocobalamin as an injection for the treatment of cyanide poisoning.

Properties

Hydroxocobalamin acetate occurs as odorless, dark-red orthorhombic needles. The injection formulations appear as clear, dark-red solutions. It has a distribution coefficient of 1.133 × 10-5 and a pKa of 7.65.

Causes of deficiency

Injection of hydroxocobalamin is used to rectify the following causes of vitamin B12 deficiency (list taken from the drug prescription label published by the U.S. Food and Drug Administration)

Pernicious anemia, is not a cause of vitamin B12 deficiency, but rather the result of vitamin B12 deficiency. 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.

Vitamin B12 group

The term "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 with folic acid, cobalamins are essential cofactors required for DNA synthesis in cells where chromosomal replication and division are occurring—most notably the bone marrow and myeloid cells. As a cofactor, cobalamins are essential for two cellular reactions: (1) the mitochondrial methylmalonyl coenzyme A mutase conversion of methylmalonic acid (MMA) to succinate, which links lipid and carbohydrate metabolism, and (2) activation of methionine synthase, which is the rate limiting step in the synthesis of methionine from homocysteine and tetrahydrofolate.[13]

Cobalamins are characterized by a porphyrin-like corrin nucleus that contains a single cobalt atom bound to a benzimidazolyl nucleotide and a variable residue (R) group. The variable R group gives rise to the four most commonly known cobalamins: CNCbl, methylcobalamin, 5-deoxyadenosylcobalamin, and OHCbl. In the serum, hydroxocobalamin and cyanocobalamin are believed to function as storage or transport forms of the molecule, whereas methylcobalamin and 5-deoxyadenosylcobalamin are the active forms of the coenzyme required for cell growth and replication.[14] Cyanocobalamin is usually converted to hydroxocobalamin in the serum, whereas hydroxocobalamin is converted to either methylcobalamin or 5-deoxyadenosyl cobalamin. Cobalamins circulate bound to serum proteins called transcobalamins (TC) and haptocorrins. Hydroxocobalamin has a higher affinity to the TC II transport protein than cyanocobalamin, or 5-deoxyadenosylcobalamin. From a biochemical point of view, two essential enzymatic reactions require vitamin B12 (cobalamin).[15][16]

Intracellular vitamin B12 is maintained in two active coenzymes, methylcobalamin and 5-deoxyadenosylcobalamin, which are both involved in specific enzymatic reactions. In the face of vitamin B12 deficiency, conversion of methylmalonyl-CoA to succinyl-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 of purines and pyrimidines and the transfer of the methyl group to cobalamin is essential for the adequate supply of tetrahydrofolate, 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 of methyltetrahydrofolate. The resulting elevated concentrations of homocysteine and MMA are often found in patients with low serum vitamin B12 and can usually be lowered with successful vitamin B12 replacement therapy. However, elevated MMA and homocysteine concentrations may persist in patients with cobalamin concentrations between 200 to 350 pg/mL.[17] 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 deoxyadenosylcobalamin.

See also

References

  1. ↑ "Hydroxocobalamin Pregnancy and Breastfeeding Warnings". drugs.com.
  2. ↑ https://www.ebi.ac.uk/chembldb/index.php/compound/results/1/chemblid/asc/tab/keyword
  3. ↑ https://www.ebi.ac.uk/chembldb/index.php/compound/results/1/chemblid/asc/tab/keyword
  4. ↑ Dart, Richard C. (1 January 2006). "Hydroxocobalamin for Acute Cyanide Poisoning: New Data from Preclinical and Clinical Studies; New Results from the Prehospital Emergency Setting". Clinical Toxicology 44 (s1): 1–3. doi:10.1080/15563650600811607. PMID 16990188.
  5. ↑ "19th WHO Model List of Essential Medicines (April 2015)" (PDF). WHO. April 2015. Retrieved May 10, 2015.
  6. ↑ Carethers, 1988
  7. ↑ Chisholm et al., 1967
  8. ↑ Freeman, 1992
  9. ↑ Markle, 1996
  10. ↑ Shepherd G, Velez LI (May 2008). "Role of hydroxocobalamin in acute cyanide poisoning". Ann Pharmacother 42 (5): 661–9. doi:10.1345/aph.1K559. PMID 18397973.
  11. ↑ Forsyth et al., 1993
  12. ↑ Riou et al., 1993
  13. ↑ Katzung, 1989
  14. ↑ Katzung, 1989
  15. ↑ Katzung, 1989
  16. ↑ Hardman, 2001
  17. ↑ Lindenbaum et al. 1994

External links

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