Hydroxocobalamin

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.

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.

Side effects

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. 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.

Mechanism of action

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:

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. 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).

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 and 350 pg/mL. 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.