Hydroxocobalamin

Last updated

Hydroxocobalamin
Hydroxocobalamin.svg
Clinical data
Other namesvitamin B12, vitamin B12a, hydroxycobalamin
AHFS/Drugs.com Monograph
MedlinePlus a605007
Routes of
administration
Oral, Intramuscular, intravenous
ATC code
Legal status
Legal status
  • NZ:Prescription only (IM ampule)
  • US: OTC (by prescription when injectable), not DEA-controlled
Pharmacokinetic data
Protein binding Very high (90%)
Metabolism Primarily liver, cobalamins are absorbed in the ileum and stored in the liver.
Elimination half-life ~6 days
Identifiers
  • Coα-[α-(5,6-dimethylbenzimidazolyl)]-
    Coβ-hydroxocobamide
CAS Number
PubChem CID
DrugBank
ChemSpider
UNII
KEGG
ChEBI
ChEMBL
CompTox Dashboard (EPA)
ECHA InfoCard 100.033.198 OOjs UI icon edit-ltr-progressive.svg
Chemical and physical data
Formula C62H89CoN13O15P
Molar mass 1346.377 g·mol−1
3D model (JSmol)
  • Cc1cc2ncn(c2cc1C)C9OC(CO)C(OP3(=O)OC(C)CNC(=O)CCC5C4=C(C)C8=NC(=CC7=NC(=C(C)C6=NC(C)(C(N4[Co](O)O3)C5(C)CC(N)=O)C(C)(CC(N)=O)C6CCC(N)=O)C(C)(CC(N)=O)C7CCC(N)=O)C(CCC(N)=O)C8(C)C)C9O
  • InChI=1S/C62H90N13O14P.Co.H2O/c1-29-20-40-41(21-30(29)2)75(28-70-40)56-52(84)53(42(27-76)87-56)89-90(85,86)88-31(3)26-69-49(83)19-15-36-50-32(4)54-58(6,7)34(12-16-43(63)77)38(71-54)22-39-35(13-17-44(64)78)59(8,23-46(66)80)55(72-39)33(5)51-37(14-18-45(65)79)61(10,25-48(68)82)62(11,74-51)57(73-50)60(36,9)24-47(67)81;;/h20-22,28,31,34-37,42,52-53,56-57,76,84H,12-19,23-27H2,1-11H3,(H15,63,64,65,66,67,68,69,71,72,73,74,77,78,79,80,81,82,83,85,86);;1H2/q;+3;/p-3 Yes check.svgY
  • Key:GTSMWDDKWYUXGH-UHFFFAOYSA-K Yes check.svgY
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Hydroxocobalamin, also known as vitamin B12a and hydroxycobalamin, is a vitamin found in food and used as a dietary supplement. [1] As a supplement it is used to treat vitamin B12 deficiency including pernicious anemia. [1] [2] Other uses include treatment for cyanide poisoning, Leber's optic atrophy, and toxic amblyopia. [3] [4] It is given by injection into a muscle or vein. [2]

Contents

Side effects are generally few. [2] They may include diarrhea, feeling sick, hot flushes, itchiness, low blood potassium, allergic reactions, and high blood pressure. [2] Normal doses are considered safe in pregnancy. [5] No overdosage or toxicity has been reported with this drug. [2] Hydroxocobalamin is the natural form of vitamin B12 and a member of the cobalamin 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 make DNA. [7]

Hydroxocobalamin was first isolated in 1949. [9] It is on the World Health Organization's List of Essential Medicines. [10] Hydroxocobalamin is available as a generic medication. [2] Commercially it is made using one of a number of types of bacteria. [11]

Medical uses

Hydroxocobalamin at standard conditions is a solid composed of dark red crystals. HydroxycobalaminSolid.JPG
Hydroxocobalamin at standard conditions is a solid composed of dark red crystals.
Hydroxocobalamin injection USP (1000 mg/mL) is a clear red liquid solution. Shown is 500 mg B-12 prepared for subcutaneous injection. Hydroxocobalamin Injection.jpg
Hydroxocobalamin injection USP (1000 μg/mL) is a clear red liquid solution. Shown is 500 μg B-12 prepared for subcutaneous injection.

Vitamin B12 deficiency

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 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. [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 ]

Cyanide poisoning

In 2006 the FDA approved hydroxocobalamin for treating smoke inhalation, which can cause cyanide poisoning. [14] Hydroxocobalamin is first line therapy for people with cyanide poisoning. [2] Hydroxocobalamin converts cyanide to the much less toxic cyanocobalamin. 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. [15]

Injectable hydroxocobalamin

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 the most common cause of vitamin B12 deficiency. [16] 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.

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. [17] [18] 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 like blood in the urine. [19]

Properties

Hydroxocobalamin acetate occurs as odorless, dark-red orthorhombic crystals. 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.[ citation needed ]

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. [20] 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). [20] [21]

Intracellular vitamin B12 is maintained in two active coenzymes, methylcobalamin and 5-deoxyadenosylcobalamin. 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. [22] 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.

Related Research Articles

<span class="mw-page-title-main">Folate</span> Vitamin B9; nutrient essential for DNA synthesis

Folate, also known as vitamin B9 and folacin, is one of the B vitamins. Manufactured folic acid, which is converted into folate by the body, is used as a dietary supplement and in food fortification as it is more stable during processing and storage. Folate is required for the body to make DNA and RNA and metabolise amino acids necessary for cell division and maturation of blood cells. As the human body cannot make folate, it is required in the diet, making it an essential nutrient. It occurs naturally in many foods. The recommended adult daily intake of folate in the U.S. is 400 micrograms from foods or dietary supplements.

<span class="mw-page-title-main">Intrinsic factor</span> Glycoprotein produced in the stomach which binds to vitamin B12

Intrinsic factor (IF), cobalamin binding intrinsic factor, also known as gastric intrinsic factor (GIF), is a glycoprotein produced by the parietal cells (in humans) or chief cells (in rodents) of the stomach. It is necessary for the absorption of vitamin B12 later on in the distal ileum of the small intestine. In humans, the gastric intrinsic factor protein is encoded by the CBLIF gene. Haptocorrin (transcobalamin I) is another glycoprotein secreted by the salivary glands which binds to vitamin B12. Vitamin B12 is acid-sensitive and in binding to haptocorrin it can safely pass through the acidic stomach to the duodenum.

B vitamins are a class of water-soluble vitamins that play important roles in cell metabolism and synthesis of red blood cells. They are a chemically diverse class of compounds; some contain sulfur and B12 contains cobalt. Dietary supplements containing all eight are referred to as a vitamin B complex. Individual B vitamins are referred to by B-number or by chemical name, such as B1 for thiamine, B2 for riboflavin, and B3 for niacin, while some are more commonly recognized by name than by number, such as pantothenic acid (B5), biotin (B7), and folate (B9).

<span class="mw-page-title-main">Pernicious anemia</span> Anemia caused by vitamin B12 deficiency

Pernicious anemia is a disease where not enough red blood cells are produced due to a deficiency of vitamin B12. Those affected often have a gradual onset. The most common initial symptoms are feeling tired and weak. Other symptoms may include shortness of breath, feeling faint, a smooth red tongue, pale skin, chest pain, nausea and vomiting, loss of appetite, heartburn, numbness in the hands and feet, difficulty walking, memory loss, muscle weakness, poor reflexes, blurred vision, clumsiness, depression, and confusion. Without treatment, some of these problems may become permanent.

<span class="mw-page-title-main">Methylmalonic acidemias</span> Medical condition

Methylmalonic acidemias, also called methylmalonic acidurias, are a group of inherited metabolic disorders, that prevent the body from properly breaking down proteins and fats. This leads to a buildup of a toxic level of methylmalonic acid in body liquids and tissues. Due to the disturbed branched-chain amino acids (BCAA) metabolism, they are among the classical organic acidemias.

<span class="mw-page-title-main">Homocystinuria</span> Medical condition

Homocystinuria or HCU is an inherited disorder of the metabolism of the amino acid methionine due to a deficiency of cystathionine beta synthase or methionine synthase. It is an inherited autosomal recessive trait, which means a child needs to inherit a copy of the defective gene from both parents to be affected. Symptoms of homocystinuria can also be caused by a deficiency of vitamins B6, B12, or folate.

The Schilling test was a medical investigation used for patients with vitamin B12 (cobalamin) deficiency. The purpose of the test was to determine how well a patient is able to absorb B12 from their intestinal tract. The test is now considered obsolete and is rarely performed, and is no longer available at many medical centers. It is named for Robert F. Schilling.

<span class="mw-page-title-main">Megaloblastic anemia</span> Medical condition

Megaloblastic anemia is a type of macrocytic anemia. An anemia is a red blood cell defect that can lead to an undersupply of oxygen. Megaloblastic anemia results from inhibition of DNA synthesis during red blood cell production. When DNA synthesis is impaired, the cell cycle cannot progress from the G2 growth stage to the mitosis (M) stage. This leads to continuing cell growth without division, which presents as macrocytosis. Megaloblastic anemia has a rather slow onset, especially when compared to that of other anemias. The defect in red cell DNA synthesis is most often due to hypovitaminosis, specifically vitamin B12 deficiency or folate deficiency. Loss of micronutrients may also be a cause.

<span class="mw-page-title-main">Methionine synthase</span> Mammalian protein found in Homo sapiens

Methionine synthase (MS, MeSe, MTR) is primarily responsible for the regeneration of methionine from homocysteine in most individuals. In humans it is encoded by the MTR gene (5-methyltetrahydrofolate-homocysteine methyltransferase). Methionine synthase forms part of the S-adenosylmethionine (SAMe) biosynthesis and regeneration cycle, and is the enzyme responsible for linking the cycle to one-carbon metabolism via the folate cycle. There are two primary forms of this enzyme, the Vitamin B12 (cobalamin)-dependent (MetH) and independent (MetE) forms, although minimal core methionine synthases that do not fit cleanly into either category have also been described in some anaerobic bacteria. The two dominant forms of the enzymes appear to be evolutionary independent and rely on considerably different chemical mechanisms. Mammals and other higher eukaryotes express only the cobalamin-dependent form. In contrast, the distribution of the two forms in Archaeplastida (plants and algae) is more complex. Plants exclusively possess the cobalamin-independent form, while algae have either one of the two, depending on species. Many different microorganisms express both the cobalamin-dependent and cobalamin-independent forms.

<span class="mw-page-title-main">Methylcobalamin</span> Form of vitamin B12

Methylcobalamin (mecobalamin, MeCbl, or MeB12) is a cobalamin, a form of vitamin B12. It differs from cyanocobalamin in that the cyano group at the cobalt is replaced with a methyl group. Methylcobalamin features an octahedral cobalt(III) centre and can be obtained as bright red crystals. From the perspective of coordination chemistry, methylcobalamin is notable as a rare example of a compound that contains metal–alkyl bonds. Nickel–methyl intermediates have been proposed for the final step of methanogenesis.

<span class="mw-page-title-main">Folate deficiency</span> Abnormally low level of folate (vitamin B9) in the body

Folate deficiency, also known as vitamin B9 deficiency, is a low level of folate and derivatives in the body. This may result in a type of anemia in which red blood cells become abnormally large and is a late finding in folate deficiency and folate deficiency anemia is the term given for this medical condition. Signs of folate deficiency are often subtle. Symptoms may include feeling tired, heart palpitations, shortness of breath, feeling faint, open sores on the tongue, loss of appetite, changes in the color of the skin or hair, irritability, and behavioral changes. Temporary reversible infertility may occur. Folate deficiency anemia during pregnancy may give rise to the birth of low weight birth premature infants and infants with neural tube defects.

<span class="mw-page-title-main">Methylmalonic acid</span> Chemical compound

Methylmalonic acid (MMA) is a dicarboxylic acid that is a C-methylated derivative of malonic acid.

Vitamin B<sub>12</sub> deficiency Disorder resulting from low blood levels of vitamin B12

Vitamin B12 deficiency, also known as cobalamin deficiency, is the medical condition in which the blood and tissue have a lower than normal level of vitamin B12. Symptoms can vary from none to severe. Mild deficiency may have few or absent symptoms. In moderate deficiency, feeling tired, headaches, soreness of the tongue, mouth ulcers, breathlessness, feeling faint, rapid heartbeat, low blood pressure, pallor, hair loss, decreased ability to think and severe joint pain and the beginning of neurological symptoms, including abnormal sensations such as pins and needles, numbness and tinnitus may occur. Severe deficiency may include symptoms of reduced heart function as well as more severe neurological symptoms, including changes in reflexes, poor muscle function, memory problems, blurred vision, irritability, ataxia, decreased smell and taste, decreased level of consciousness, depression, anxiety, guilt and psychosis. If left untreated, some of these changes can become permanent. Temporary infertility, reversible with treatment, may occur. A late finding type of anemia known as megaloblastic anemia is often but not always present. In exclusively breastfed infants of vegan mothers, undetected and untreated deficiency can lead to poor growth, poor development, and difficulties with movement.

Vitamin B<sub><small>12</small></sub> Vitamin used in animal cells metabolism

Vitamin B12, also known as cobalamin, is a water-soluble vitamin involved in metabolism. It is one of eight B vitamins. It is required by animals, which use it as a cofactor in DNA synthesis, and in both fatty acid and amino acid metabolism. It is important in the normal functioning of the nervous system via its role in the synthesis of myelin, and in the circulatory system in the maturation of red blood cells in the bone marrow. Plants do not need cobalamin and carry out the reactions with enzymes that are not dependent on it.

<span class="mw-page-title-main">Cyanocobalamin</span> Form of vitamin B-12

Cyanocobalamin is a form of vitamin B
12
used to treat and prevent vitamin B
12
deficiency
except in the presence of cyanide toxicity. The deficiency may occur in pernicious anemia, following surgical removal of the stomach, with fish tapeworm, or due to bowel cancer. It is used by mouth, by injection into a muscle, or as a nasal spray.

<span class="mw-page-title-main">MTRR (gene)</span> Protein-coding gene in the species Homo sapiens

Methionine synthase reductase, also known as MSR, is an enzyme that in humans is encoded by the MTRR gene.

<span class="mw-page-title-main">Haptocorrin</span> Protein-coding gene in the species Homo sapiens

Haptocorrin (HC) also known as transcobalamin-1 (TC-1) or cobalophilin is a transcobalamin protein that in humans is encoded by the TCN1 gene. One essential function of haptocorrin is protection of the acid-sensitive vitamin B12 while it moves through the stomach. A second function is serum HC binding of the great majority of circulating vitamin B12, rendering it unavailable for take-up by cells. This is conjectured to be a circulating storage function.

<span class="mw-page-title-main">Nutritional neuroscience</span> Scientific discipline

Nutritional neuroscience is the scientific discipline that studies the effects various components of the diet such as minerals, vitamins, protein, carbohydrates, fats, dietary supplements, synthetic hormones, and food additives have on neurochemistry, neurobiology, behavior, and cognition.

<span class="mw-page-title-main">Imerslund–Gräsbeck syndrome</span> Medical condition

Imerslund–Gräsbeck syndrome is a rare autosomal recessive, familial form of vitamin B12 deficiency caused by malfunction of the "Cubam" receptor located in the terminal ileum. This receptor is composed of two proteins, amnionless (AMN), and cubilin. A defect in either of these protein components can cause this syndrome. This is a rare disease, with a prevalence about 1 in 200,000, and is usually seen in patients of European ancestry.

Relatively speaking, the brain consumes an immense amount of energy in comparison to the rest of the body. The mechanisms involved in the transfer of energy from foods to neurons are likely to be fundamental to the control of brain function. Human bodily processes, including the brain, all require both macronutrients, as well as micronutrients.

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