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Identification
NameHydroxocobalamin
Accession NumberDB00200  (APRD01022)
TypeSmall Molecule
GroupsApproved
Description

Injectable form of vitamin B 12 that has been used therapeutically to treat vitamin B 12 deficiency. [PubChem]

Structure
Thumb
Synonyms
Hydroxocobalamin
Hydroxycobalamin
OH-Cbl
Vitamin B-12b
External Identifiers Not Available
Prescription Products
NameDosageStrengthRouteLabellerMarketing StartMarketing End
Cyanokitinjection, powder, lyophilized, for solution2.5 g/100mLintravenousMeridian Medical Technologies, Inc.2009-08-31Not applicableUs 0a2ef1ad1c84951dc1392a8bbe1f3cb241c91ed59e44ad8268635315440d978c
Cyanokitpowder for solution2.5 gintravenousEmd Serono A Division Of Emd Inc Canada2011-04-072014-09-30Canada 5f16b84899037e23705f146ff57e3794121879cb055f0954756d94bc690476b4
Cyanokitpowder for solution5 gintravenousEmd Serono A Division Of Emd Inc Canada2012-10-19Not applicableCanada 5f16b84899037e23705f146ff57e3794121879cb055f0954756d94bc690476b4
Cyanokitinjection, powder, lyophilized, for solution5 g/250mLintravenousMeridian Medical Technologies, Inc.2011-10-01Not applicableUs 0a2ef1ad1c84951dc1392a8bbe1f3cb241c91ed59e44ad8268635315440d978c
Hydro Cobex Inj 1000mcg/mlliquid1 mgintramuscularKripps Pharmacy Ltd.1979-12-31Not applicableCanada 5f16b84899037e23705f146ff57e3794121879cb055f0954756d94bc690476b4
Hydroxocobalamin Inj 1000mcg/mlliquid1 mgintramuscularE L Stickley And Co Ltd.1968-12-311996-09-09Canada 5f16b84899037e23705f146ff57e3794121879cb055f0954756d94bc690476b4
Hydroxy Cobal Inj 1000mcg/mlliquid1 mgintramuscularMerit Pharmaceuticals1984-12-31Not applicableCanada 5f16b84899037e23705f146ff57e3794121879cb055f0954756d94bc690476b4
Generic Prescription ProductsNot Available
Over the Counter ProductsNot Available
International Brands
NameCompany
Alpha-RedisolMerck
HydrocobamineNycomed
Brand mixturesNot Available
SaltsNot Available
Categories
UNIIQ40X8H422O
CAS number13422-51-0
WeightAverage: 1346.3551
Monoisotopic: 1345.567070949
Chemical FormulaC62H89CoN13O15P
InChI KeyInChIKey=YOZNUFWCRFCGIH-WZHZPDAFSA-K
InChI
InChI=1S/C62H90N13O14P.Co.H2O/c1-29-20-39-40(21-30(29)2)75(28-70-39)57-52(84)53(41(27-76)87-57)89-90(85,86)88-31(3)26-69-49(83)18-19-59(8)37(22-46(66)80)56-62(11)61(10,25-48(68)82)36(14-17-45(65)79)51(74-62)33(5)55-60(9,24-47(67)81)34(12-15-43(63)77)38(71-55)23-42-58(6,7)35(13-16-44(64)78)50(72-42)32(4)54(59)73-56;;/h20-21,23,28,31,34-37,41,52-53,56-57,76,84H,12-19,22,24-27H2,1-11H3,(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/t31-,34-,35-,36-,37+,41-,52-,53-,56-,57+,59-,60+,61+,62+;;/m1../s1
IUPAC Name
hydroxy[(1R,2R,3S,4S,8S,9S,14S,18R,19R)-4,9,14-tris(2-carbamoylethyl)-3,8,19-tris(carbamoylmethyl)-18-(2-{[(2R)-2-{[(2R,3S,4R,5S)-5-(5,6-dimethyl-1H-1,3-benzodiazol-1-yl)-4-hydroxy-2-(hydroxymethyl)oxolan-3-yl phosphonato]oxy}propyl]carbamoyl}ethyl)-2,3,6,8,13,13,16,18-octamethyl-20,21,22,23-tetraazapentacyclo[15.2.1.1²,⁵.1⁷,¹⁰.1¹²,¹⁵]tricosa-5(23),6,10(22),11,15(21),16-hexaen-20-yl]cobaltylium
SMILES
[H]O[Co+]N1\C2=C(C)/C3=N/C(=C\C4=N\C(=C(C)/C5=N[C@@](C)([C@@]1([H])[C@H](CC(=O)N)[C@@]2(C)CCC(=O)NC[C@@H](C)OP(=O)([O-])O[C@H]1[C@@H](O)[C@H](O[C@@H]1CO)N1C=NC2=CC(C)=C(C)C=C12)[C@@](C)(CC(N)=O)[C@@H]5CCC(=O)N)\[C@@](C)(CC(=O)N)[C@@H]4CCC(=O)N)/C(C)(C)[C@@H]3CCC(=O)N
Taxonomy
DescriptionThis compound belongs to the class of organic compounds known as cobalamin derivatives. These are organic compounds containing a corrin ring, a cobalt atom, an a nucleotide moiety. Cobalamin Derivatives are actually derived from vitamin B12.
KingdomOrganic compounds
Super ClassOrganoheterocyclic compounds
ClassTetrapyrroles and derivatives
Sub ClassCorrinoids
Direct ParentCobalamin derivatives
Alternative Parents
Substituents
  • Cobalamin
  • Metallotetrapyrrole skeleton
  • 1-ribofuranosylbenzimidazole
  • N-glycosyl compound
  • Glycosyl compound
  • Monosaccharide phosphate
  • Benzimidazole
  • Phosphoethanolamine
  • Dialkyl phosphate
  • Fatty acyl
  • Benzenoid
  • Alkyl phosphate
  • Phosphoric acid ester
  • Organic phosphoric acid derivative
  • Organic phosphate
  • N-substituted imidazole
  • Monosaccharide
  • Fatty amide
  • Heteroaromatic compound
  • Pyrroline
  • Pyrrolidine
  • Oxolane
  • Imidazole
  • Azole
  • Secondary carboxylic acid amide
  • Secondary alcohol
  • Primary carboxylic acid amide
  • Ketimine
  • Carboxamide group
  • Oxacycle
  • Azacycle
  • Organic metal salt
  • Organic 1,3-dipolar compound
  • Propargyl-type 1,3-dipolar organic compound
  • Carboxylic acid derivative
  • Carboxylic acid amide
  • Hydrocarbon derivative
  • Organic transition metal salt
  • Organic cobalt salt
  • Organic salt
  • Primary alcohol
  • Organooxygen compound
  • Organonitrogen compound
  • Imine
  • Carbonyl group
  • Alcohol
  • Organic zwitterion
  • Aromatic heteropolycyclic compound
Molecular FrameworkAromatic heteropolycyclic compounds
External Descriptors
Pharmacology
IndicationFor treatment of pernicious anemia and the prevention and treatment of vitamin B12 deficiency arising from alcoholism, malabsorption, tapeworm infestation, celiac, hyperthyroidism, hepatic-biliary tract disease, persistent diarrhea, ileal resection, pancreatic cancer, renal disease, prolonged stress, vegan diets, macrobiotic diets or other restrictive diets. Also for the treatment of known or suspected cyanide poisoning.
PharmacodynamicsHydroxocobalamin is a synthetic, injectable form of Vitamin B12. Hydroxocobalamin is actually a precursor of two cofactors or vitamins (Vitamin B12 and Methylcobalamin) which are involved in various biological systems in man. Vitamin B12 is required for the conversion of methylmalonate to succinate. Deficiency of this enzyme could therefore interfere with the production of lipoprotein in myelin sheath tissue and so give rise to neurological lesions. The second cofactor, Methylcobalamin, is necessary for the conversion of homocysteine to methionine which is essential for the metabolism of folic acid. Deficiency of tetrahydrafolate leads to reduced synthesis of thymidylate resulting in reduced synthesis of DNA which is essential for cell maturation. Vitamin B12 is also concerned in the maintenance of sulphydryl groups in reduced form, deficiency leading to decreased amounts of reduced SH content of erythrocytes and liver cells. Overall, vitamin B12 acts as a coenzyme for various metabolic functions, including fat and carbohydrate metabolism and protein synthesis. It is necessary for growth, cell replication, hematopoiesis, and nucleoprotein as well as myelin synthesis. This is largely due to its effects on metabolism of methionine folic acid, and malonic acid.
Mechanism of actionVitamin B12 exists in four major forms referred to collectively as cobalamins; deoxyadenosylcobalamin, methylcobalamin, hydroxocobalamin, and cyanocobalamin. Two of these, methylcobalamin and 5-deoxyadenosyl cobalamin, are primarily used by the body. Methionine synthase needs methylcobalamin as a cofactor. This enzyme is involved in the conversion of the amino acid homocysteine into methionine. Methionine in turn is required for DNA methylation. 5-Deoxyadenosyl cobalamin is a cofactor needed by the enzyme that converts L-methylmalonyl-CoA to succinyl-CoA. This conversion is an important step in the extraction of energy from proteins and fats. Furthermore, succinyl CoA is necessary for the production of hemoglobin, the substances that carries oxygen in red blood cells.
AbsorptionReadily absorbed from the gastrointestinal tract, except in malabsorption syndromes. Vitamin B12 is absorbed in the lower half of the ileum.
Volume of distributionNot Available
Protein bindingVery high (90%). Cobalamins are extensively bound to two specific plasma proteins called transcobalamin 1 and 2; 70% to transcobalamin 1, 5% to transcobalamin 2.
Metabolism

Primarily hepatic. Cobalamins are absorbed in the ileum and stored in the liver. They continuously undergo enterohepatic recycling via secretion in the bile. Part of a dose is excreted in the urine, most of it in the first 8 hours.

Route of eliminationEach hydroxocobalamin molecule can bind one cyanide ion by substituting it for the hydroxo ligand linked to the trivalent cobalt ion, to form cyanocobalamin, which is then excreted in the urine.
Half lifeApproximately 6 days (peak plasma concentration after 8-12 hours from oral administration)
ClearanceNot Available
ToxicityNot Available
Affected organisms
  • Humans and other mammals
PathwaysNot Available
SNP Mediated EffectsNot Available
SNP Mediated Adverse Drug ReactionsNot Available
ADMET
Predicted ADMET features
PropertyValueProbability
Human Intestinal Absorption+0.6922
Blood Brain Barrier-0.712
Caco-2 permeable-0.6447
P-glycoprotein substrateSubstrate0.8579
P-glycoprotein inhibitor INon-inhibitor0.6643
P-glycoprotein inhibitor IIInhibitor0.5
Renal organic cation transporterNon-inhibitor0.9054
CYP450 2C9 substrateNon-substrate0.8081
CYP450 2D6 substrateNon-substrate0.8083
CYP450 3A4 substrateSubstrate0.6458
CYP450 1A2 substrateNon-inhibitor0.8778
CYP450 2C9 inhibitorNon-inhibitor0.8836
CYP450 2D6 inhibitorNon-inhibitor0.8717
CYP450 2C19 inhibitorNon-inhibitor0.709
CYP450 3A4 inhibitorInhibitor0.5841
CYP450 inhibitory promiscuityLow CYP Inhibitory Promiscuity0.8028
Ames testNon AMES toxic0.5675
CarcinogenicityNon-carcinogens0.7831
BiodegradationNot ready biodegradable0.9729
Rat acute toxicity2.6700 LD50, mol/kg Not applicable
hERG inhibition (predictor I)Weak inhibitor0.8966
hERG inhibition (predictor II)Non-inhibitor0.6952
ADMET data is predicted using admetSAR, a free tool for evaluating chemical ADMET properties. (23092397 )
Pharmacoeconomics
Manufacturers
  • Merck and co inc
  • Merck sante sas
  • Abraxis pharmaceutical products
  • Watson laboratories inc
  • Bel mar laboratories inc
Packagers
Dosage forms
FormRouteStrength
Injection, powder, lyophilized, for solutionintravenous2.5 g/100mL
Injection, powder, lyophilized, for solutionintravenous5 g/250mL
Powder for solutionintravenous2.5 g
Powder for solutionintravenous5 g
Liquidintramuscular1 mg
Prices
Unit descriptionCostUnit
Cyanokit 5 g kit812.5USD kit
Hydroxocobalamin 1000 mcg/ml1.28USD ml
DrugBank does not sell nor buy drugs. Pricing information is supplied for informational purposes only.
Patents
CountryPatent NumberApprovedExpires (estimated)
United States58344481996-11-142016-11-14
Properties
StateSolid
Experimental PropertiesNot Available
Predicted Properties
PropertyValueSource
Water Solubility0.0146 mg/mLALOGPS
logP2.53ALOGPS
logS-5ALOGPS
pKa (Strongest Acidic)1.84ChemAxon
pKa (Strongest Basic)8.78ChemAxon
Physiological Charge3ChemAxon
Number of Rings8ChemAxon
Bioavailability0ChemAxon
Rule of FiveYesChemAxon
Ghose FilterYesChemAxon
Veber's RuleYesChemAxon
MDDR-like RuleYesChemAxon
Spectra
Mass Spec (NIST)Not Available
SpectraNot Available
References
Synthesis Reference

Takayuki Hirayama, Takashi Kiyota, “Process for production of hydroxocobalamin.” U.S. Patent US5338418, issued June, 1982.

US5338418
General References
  1. Link
  2. Seetharam B, Yammani RR: Cobalamin transport proteins and their cell-surface receptors. Expert Rev Mol Med. 2003 Jun 13;5(18):1-18. Pubmed
External Links
ATC CodesB03BA03V03AB33
AHFS Codes
  • 88:08.00
PDB EntriesNot Available
FDA labelNot Available
MSDSDownload (73.6 KB)
Interactions
Drug Interactions
Drug
ChloramphenicolThe therapeutic efficacy of Hydroxocobalamin can be decreased when used in combination with Chloramphenicol.
Food InteractionsNot Available

Targets

1. Methionine synthase

Kind: Protein

Organism: Human

Pharmacological action: yes

Actions: cofactor

Components

Name UniProt ID Details
Methionine synthase Q99707 Details

References:

  1. Kolhouse JF, Utley C, Stabler SP, Allen RH: Mechanism of conversion of human apo- to holomethionine synthase by various forms of cobalamin. J Biol Chem. 1991 Dec 5;266(34):23010-5. Pubmed
  2. Ogier de Baulny H, Gerard M, Saudubray JM, Zittoun J: Remethylation defects: guidelines for clinical diagnosis and treatment. Eur J Pediatr. 1998 Apr;157 Suppl 2:S77-83. Pubmed
  3. Tkachuck RD, Weinstein PP, Mueller JF: Metabolic fate of cyanocobalamin taken up by Spirometra mansonoides spargana. J Parasitol. 1977 Aug;63(4):694-700. Pubmed
  4. Quadros EV, Jacobsen DW: The dynamics of cobalamin utilization in L-1210 mouse leukemia cells: a model of cellular cobalamin metabolism. Biochim Biophys Acta. 1995 Jun 9;1244(2-3):395-403. Pubmed
  5. Rosenblatt DS, Thomas IT, Watkins D, Cooper BA, Erbe RW: Vitamin B12 responsive homocystinuria and megaloblastic anemia: heterogeneity in methylcobalamin deficiency. Am J Med Genet. 1987 Feb;26(2):377-83. Pubmed

2. Methylmalonyl-CoA mutase, mitochondrial

Kind: Protein

Organism: Human

Pharmacological action: yes

Actions: cofactor

Components

Name UniProt ID Details
Methylmalonyl-CoA mutase, mitochondrial P22033 Details

References:

  1. Willard HF, Rosenberg LE: Inborn errors of cobalamin metabolism: effect of cobalamin supplementation in culture on methylmalonyl CoA mutase activity in normal and mutant human fibroblasts. Biochem Genet. 1979 Feb;17(1-2):57-75. Pubmed
  2. Dayem LC, Carney JR, Santi DV, Pfeifer BA, Khosla C, Kealey JT: Metabolic engineering of a methylmalonyl-CoA mutase-epimerase pathway for complex polyketide biosynthesis in Escherichia coli. Biochemistry. 2002 Apr 23;41(16):5193-201. Pubmed
  3. Mayatepek E, Hoffmann GF, Baumgartner R, Schulze A, Jakobs C, Trefz FK, Bremer HJ: Atypical vitamin B12-unresponsive methylmalonic aciduria in sibship with severe progressive encephalomyelopathy: a new genetic disease? Eur J Pediatr. 1996 May;155(5):398-403. Pubmed
  4. Tkachuck RD, Weinstein PP, Mueller JF: Metabolic fate of cyanocobalamin taken up by Spirometra mansonoides spargana. J Parasitol. 1977 Aug;63(4):694-700. Pubmed
  5. Quadros EV, Jacobsen DW: The dynamics of cobalamin utilization in L-1210 mouse leukemia cells: a model of cellular cobalamin metabolism. Biochim Biophys Acta. 1995 Jun 9;1244(2-3):395-403. Pubmed
  6. Chen X, Ji ZL, Chen YZ: TTD: Therapeutic Target Database. Nucleic Acids Res. 2002 Jan 1;30(1):412-5. Pubmed

3. Methionine synthase reductase

Kind: Protein

Organism: Human

Pharmacological action: unknown

Actions: other

Components

Name UniProt ID Details
Methionine synthase reductase Q9UBK8 Details

References:

  1. Overington JP, Al-Lazikani B, Hopkins AL: How many drug targets are there? Nat Rev Drug Discov. 2006 Dec;5(12):993-6. Pubmed
  2. Imming P, Sinning C, Meyer A: Drugs, their targets and the nature and number of drug targets. Nat Rev Drug Discov. 2006 Oct;5(10):821-34. Pubmed

4. Methylmalonic aciduria type A protein, mitochondrial

Kind: Protein

Organism: Human

Pharmacological action: unknown

Actions: other/unknown

Components

Name UniProt ID Details
Methylmalonic aciduria type A protein, mitochondrial Q8IVH4 Details

References:

  1. Overington JP, Al-Lazikani B, Hopkins AL: How many drug targets are there? Nat Rev Drug Discov. 2006 Dec;5(12):993-6. Pubmed
  2. Imming P, Sinning C, Meyer A: Drugs, their targets and the nature and number of drug targets. Nat Rev Drug Discov. 2006 Oct;5(10):821-34. Pubmed
  3. Manoli I, Venditti CP: Methylmalonic Acidemia Pubmed

5. Transcobalamin-1

Kind: Protein

Organism: Human

Pharmacological action: unknown

Actions: other

Components

Name UniProt ID Details
Transcobalamin-1 P20061 Details

References:

  1. MacDonald CM, Farquharson J, Bessent RG, Adams JF: The forms of vitamin B12 on the transcobalamins. Clin Sci Mol Med. 1977 Feb;52(2):215-8. Pubmed
  2. Rothenberg SP, Marcoullis GP, Schwarz S, Lader E: Measurement of cyanocobalamin in serum by a specific radioimmunoassay. J Lab Clin Med. 1984 Jun;103(6):959-72. Pubmed

6. Protein amnionless

Kind: Protein

Organism: Human

Pharmacological action: unknown

Actions: other

Components

Name UniProt ID Details
Protein amnionless Q9BXJ7 Details

References:

  1. Overington JP, Al-Lazikani B, Hopkins AL: How many drug targets are there? Nat Rev Drug Discov. 2006 Dec;5(12):993-6. Pubmed
  2. Imming P, Sinning C, Meyer A: Drugs, their targets and the nature and number of drug targets. Nat Rev Drug Discov. 2006 Oct;5(10):821-34. Pubmed
  3. Seetharam B, Yammani RR: Cobalamin transport proteins and their cell-surface receptors. Expert Rev Mol Med. 2003 Jun 13;5(18):1-18. Pubmed

7. Cubilin

Kind: Protein

Organism: Human

Pharmacological action: unknown

Actions: other

Components

Name UniProt ID Details
Cubilin O60494 Details

References:

  1. Overington JP, Al-Lazikani B, Hopkins AL: How many drug targets are there? Nat Rev Drug Discov. 2006 Dec;5(12):993-6. Pubmed
  2. Imming P, Sinning C, Meyer A: Drugs, their targets and the nature and number of drug targets. Nat Rev Drug Discov. 2006 Oct;5(10):821-34. Pubmed
  3. Seetharam B, Yammani RR: Cobalamin transport proteins and their cell-surface receptors. Expert Rev Mol Med. 2003 Jun 13;5(18):1-18. Pubmed

8. Cob(I)yrinic acid a,c-diamide adenosyltransferase, mitochondrial

Kind: Protein

Organism: Human

Pharmacological action: unknown

Actions: other

Components

Name UniProt ID Details
Cob(I)yrinic acid a,c-diamide adenosyltransferase, mitochondrial Q96EY8 Details

References:

  1. Overington JP, Al-Lazikani B, Hopkins AL: How many drug targets are there? Nat Rev Drug Discov. 2006 Dec;5(12):993-6. Pubmed
  2. Imming P, Sinning C, Meyer A: Drugs, their targets and the nature and number of drug targets. Nat Rev Drug Discov. 2006 Oct;5(10):821-34. Pubmed

9. Methylmalonic aciduria and homocystinuria type C protein

Kind: Protein

Organism: Human

Pharmacological action: unknown

Actions: other/unknown

Components

Name UniProt ID Details
Methylmalonic aciduria and homocystinuria type C protein Q9Y4U1 Details

References:

  1. Overington JP, Al-Lazikani B, Hopkins AL: How many drug targets are there? Nat Rev Drug Discov. 2006 Dec;5(12):993-6. Pubmed
  2. Imming P, Sinning C, Meyer A: Drugs, their targets and the nature and number of drug targets. Nat Rev Drug Discov. 2006 Oct;5(10):821-34. Pubmed
  3. Lerner-Ellis JP, Tirone JC, Pawelek PD, Dore C, Atkinson JL, Watkins D, Morel CF, Fujiwara TM, Moras E, Hosack AR, Dunbar GV, Antonicka H, Forgetta V, Dobson CM, Leclerc D, Gravel RA, Shoubridge EA, Coulton JW, Lepage P, Rommens JM, Morgan K, Rosenblatt DS: Identification of the gene responsible for methylmalonic aciduria and homocystinuria, cblC type. Nat Genet. 2006 Jan;38(1):93-100. Epub 2005 Nov 27. Pubmed

Carriers

1. Transcobalamin-2

Kind: Protein

Organism: Human

Pharmacological action: unknown

Actions: substrate

Components

Name UniProt ID Details
Transcobalamin-2 P20062 Details

References:

  1. Begley JA, Colligan PD, Chu RC: Transcobalamin II mediated delivery of albumin-bound hydroxocobalamin to human liver cells. Proc Soc Exp Biol Med. 1993 Nov;204(2):206-10. Pubmed
  2. Skouby AP, Hippe E, Olesen H: Antibody to transcobalamin II and B12 binding capacity in patients treated with hydroxocobalamin. Blood. 1971 Dec;38(6):769-74. Pubmed
  3. Hippe E, Olesen H, Skouby A: [Occurrence of antibodies against transcobalamin II in relation to the number of and the intervals between depot therapy with hydroxocobalamin] Nord Med. 1970 Dec 3;84(49):1570. Pubmed
  4. Brown KL, Marques HM, Jacobsen DW: Heteronuclear NMR studies of cobalamins. 31P NMR observations of cobalamins bound to a haptocorrin from chicken serum. J Biol Chem. 1988 Feb 5;263(4):1872-7. Pubmed
  5. Chu RC, Begley JA, Colligan PD, Hall CA: The methylcobalamin metabolism of cultured human fibroblasts. Metabolism. 1993 Mar;42(3):315-9. Pubmed
  6. Seetharam B, Yammani RR: Cobalamin transport proteins and their cell-surface receptors. Expert Rev Mol Med. 2003 Jun 13;5(18):1-18. Pubmed

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Drug created on June 13, 2005 07:24 / Updated on September 16, 2013 17:08