Toxicokinetics of hydroxocobalamin were studied in rats and in dogs after single administration. In dogs, the AUCs of free cobalamins-(III) and total cobalamins-(III) increased proportionally to the dose. Mean Cmax measured for free- and total cobalamins-(III) were 1 to 5 fold higher than those measured in humans treated with 5.0 and 10.0 g hydroxocobalamin. Terminal half-lives reached approximately 6 and 8 hours for free and total cobalamins-(III), respectively in dogs. Corresponding figures in rats amounted to 3 and 5 hours. In dogs, the clearance of total cobalamins-(III) (0.064 to 0.083 L/h/kg) was 6-7 fold lower than clearance of free cobalamins-(III).
The binding of hydroxocobalamin to proteins may be regarded as reversible metabolism. Hydroxocobalamin also reacts with cyanide thereby forming cyanocobalamin. This complex is highly stable and is therefore regarded as a physiological end product of hydroxocobalamin especially during cyanide intoxication.
Concurrent administration of chloramphenicol and vitamin B12 reportedly may antagonize the hematopoietic response to vitamin B12 in vitamin B12-deficient patients. The hematologic response to vitamin B12 in patients receiving both drugs should be carefully monitored and alternate anti-infectives should be considered. /Vitamin B12/
Prednisone has been reported to increase the absorption of vitamin B12 and secretion of intrinsic factor (IF) in a few patients with pernicious anemia, but not in patients with partial or total gastrectomy. The clinical importance of these findings is unknown. /Vitamin B12/
Ascorbic acid may destroy substantial amounts of dietary vitamin B12 in vitro; this possibility should be considered when large doses of ascorbic acid are ingested within 1 hour of oral vitamin B12 administration. /Vitamin B12/
Absorption of vitamin B12 from the GI tract may be decreased by aminoglycoside antibiotics, colchicine, extended-release potassium preparations, aminosalicylic acid and its salts, anticonvulsants (e.g., phenytoin, phenobarbital, primidone), cobalt irradiation of the small bowel, and by excessive alcohol intake lasting longer than 2 weeks. Neomycin-induced malabsorption of vitamin B12 may be increased by concurrent administration of colchicine. /Vitamin B12
Caution should be exercised when administering other cyanide antidotes simultaneously with Cyanokit, as the safety of coadministration has not been established. If a decision is made to administer another cyanide antidote with Cyanokit, these drugs should not be administered concurrently in the same IV line.
The possibility of direct transport of hydroxocobalamin from the nasal cavity into the cerebrospinal fluid after nasal administration in rats was investigated and the results were compared with a human study. Hydroxocobalamin was given to rats (n=8) both intranasally (214 ug/rat) and intravenously (49.5 ug/rat) into the jugular vein using a Vascular Access Port (VAP). Prior to and after drug administration, blood and cerebrospinal fluid samples were taken and analysed by radioimmunoassay. The AUCcerebrospinal fluid/AUCplasma ratio after nasal delivery does not differ from the ratio after intravenous infusion, indicating that hydroxocobalamin enters the cerebrospinal fluid via the blood circulation across the blood-brain barrier (BBB). This same transport route is confirmed by the cumulative AUC-time profiles in cerebrospinal fluid and plasma, demonstrating a 30 min delay between plasma absorption and cerebrospinal fluid uptake of hydroxocobalamin in rats and in a comparative human study. The present results in rats show that there is no additional uptake of hydroxocobalamin in the cerebrospinal fluid after nasal delivery compared to intravenous administration, which is in accordance with the results found in humans.
Fifty percent of the administered dose of hydroxocobalamin disappears from the injection site in 2.5 hours. Hydroxocobalamin is bound to plasma proteins and stored in the liver. It is excreted in the bile and undergoes some enterohepatic recycling. Within 72 hours after injection of 500 to 1000 mcg of hydroxocobalamin, 16 to 66 percent of the injected dose may appear in the urine. The major portion is excreted within the first 24 hours.
Hydroxocobalamin is absorbed more slowly from the site of injection than is cyanocobalamin and there is some evidence that liver uptake of hydroxocobalamin may be greater than that of cyanocobalamin. It is believed that the increased retention of hydroxocobalamin compared with that of cyanocobalamin results from the greater affinity of hydroxocobalamin for both specific and nonspecific binding proteins in blood and tissues, as well as to its slower absorption from the injection site.
In the presence of gastric acid and pancreatic proteases, dietary vitamin B12 is released from food and salivary binding protein and bound to gastric intrinsic factor. When the vitamin B12-intrinsic factor complex reaches the ileum, it interacts with a receptor on the mucosal cell surface and is actively transported into circulation. Adequate intrinsic factor, bile, and sodium bicarbonate (to provide a suitable pH) all are required for ileal transport of vitamin B12. Vitamin B12 deficiency in adults is rarely the result of a deficient diet per se; rather, it usually reflects a defect in one or another aspect of this complex sequence of absorption. Achlorhydria and decreased secretion of intrinsic factor by parietal cells secondary to gastric atrophy or gastric surgery is a common cause of vitamin B12 deficiency in adults. Antibodies to parietal cells or intrinsic factor complex also can play a prominent role in producing a deficiency. A number of intestinal diseases can interfere with absorption, including pancreatic disorders (loss of pancreatic protease secretion), bacterial overgrowth, intestinal parasites, sprue, and localized damage to ileal mucosal cells by disease or as a result of surgery. /Vitamin B-12/
Section 1. Chemical Product and Company Identification Hydroxocobalamin Common Name/ Trade Name Hydroxocobalamin Section 4. First Aid Measures Eye Contact Check for and remove any contact lenses. In case of contact, immediately flush eyes with plenty of water for at least 15 minutes. Cold water may be used. Get medical attention. Skin Contact In case of contact, immediately flush skin with plenty of water. Cover the irritated skin with an emollient. Remove contaminated clothing and shoes. Cold water may be used.Wash clothing before reuse. Thoroughly clean shoes before reuse. Get medical attention. Serious Skin Contact Wash with a disinfectant soap and cover the contaminated skin with an anti-bacterial cream. Seek medical attention. Inhalation If inhaled, remove to fresh air. If not breathing, give artificial respiration. If breathing is difficult, give oxygen. Get medical attention. Serious Inhalation Not available. Ingestion Do NOT induce vomiting unless directed to do so by medical personnel. Never give anything by mouth to an unconscious person. If large quantities of this material are swallowed, call a physician immediately. Loosen tight clothing such as a collar, tie, belt or waistband. Serious Ingestion Not available. Section 5. Fire and Explosion Data Flammability of the Product May be combustible at high temperature. Auto-Ignition Temperature Not available. Flash Points Not available. Flammable Limits Not available. Products of Combustion These products are carbon oxides (CO, CO2), nitrogen oxides (NO, NO2...). Some metallic oxides. Fire Hazards in Presence of Slightly flammable to flammable in presence of heat. Various Substances Non-flammable in presence of shocks. Explosion Hazards in Presence Risks of explosion of the product in presence of mechanical impact: Not available. of Various Substances Risks of explosion of the product in presence of static discharge: Not available. Fire Fighting Media SMALL FIRE: Use DRY chemical powder. and Instructions LARGE FIRE: Use water spray, fog or foam. Do not use water jet. Special Remarks on Not available. Fire Hazards Special Remarks on Explosion Not available. Hazards Section 6. Accidental Release Measures Small Spill Use appropriate tools to put the spilled solid in a convenient waste disposal container. Finish cleaning by spreading water on the contaminated surface and dispose of according to local and regional authority requirements. Large Spill Use a shovel to put the material into a convenient waste disposal container. Finish cleaning by spreading water on the contaminated surface and allow to evacuate through the sanitary system. Hydroxocobalamin Section 7. Handling and Storage Precautions Keep away from heat. Keep away from sources of ignition. Empty containers pose a fire risk, evaporate the residue under a fume hood. Ground all equipment containing material. Do not breathe dust. Wear suitable protective clothing. In case of insufficient ventilation, wear suitable respiratory equipment. If you feel unwell, seek medical attention and show the label when possible. Avoid contact with skin and eyes. Storage Keep container tightly closed. Keep container in a cool, well-ventilated area. Do not store above 15°C (59°F). Section 8. Exposure Controls/Personal Protection Engineering Controls Use process enclosures, local exhaust ventilation, or other engineering controls to keep airborne levels below recommended exposure limits. If user operations generate dust, fume or mist, use ventilation to keep exposure to airborne contaminants below the exposure limit. Personal Protection Splash goggles. Lab coat. Dust respirator. Be sure to use an approved/certified respirator or equivalent. Gloves. Personal Protection in Case of Splash goggles. Full suit. Dust respirator. Boots. Gloves. A self contained breathing apparatus should be used a Large Spill to avoid inhalation of the product. Suggested protective clothing might not be sufficient; consult a specialist BEFORE handling this product. Exposure Limits Not available. Section 9. Physical and Chemical Properties Physical state and appearance Solid. Odor Odorless or has not more than slight acetone odor Taste Not available. Molecular Weight 1346.38 g/mole Color Red. pH (1% soln/water) Not available. Boiling Point Not available. Melting Point Not available. Critical Temperature Not available. Not available. Specific Gravity Vapor Pressure Not applicable. Vapor Density Not available. Volatility Not available. Odor Threshold Not available. Water/Oil Dist. Coeff. Not available. Ionicity (in Water) Not available. See solubility in water. Dispersion Properties Solubility Soluble in cold water. Insoluble in diethyl ether, acetone. Section 10. Stability and Reactivity Data The product is stable. Stability Instability Temperature Not available. Elevated temperatures, light, incompatible materials Conditions of Instability Incompatibility with various Not available. substances Hydroxocobalamin Not available. Corrosivity Special Remarks on Light sensitive. Reactivity Special Remarks on Not available. Corrosivity Will not occur. Polymerization Section 11. Toxicological Information Routes of Entry Inhalation. Ingestion. Toxicity to Animals LD50: Not available. LC50: Not available. Chronic Effects on Humans Not available. Other Toxic Effects on Hazardous in case of skin contact (irritant), of ingestion, of inhalation. Humans Slightly hazardous in case of skin contact (sensitizer). Special Remarks on Not available. Toxicity to Animals Special Remarks on Crosses the placenta from mother to fetus Chronic Effects on Humans Special Remarks on other Acute Potential Health Effects: Toxic Effects on Humans Skin: May cause skin irritation. May cause allergic reactions. Inhalation: Dust May cause respiratory tract irritation. Eyes: Dust may cause eye irritation. Ingestion: May cause digestive tract irritation. The toxicological properties of this substance have not been fully investigated. Section 12. Ecological Information Ecotoxicity Not available. BOD5 and COD Not available. Products of Biodegradation Possibly hazardous short term degradation products are not likely. However, long term degradation products may arise. Toxicity of the Products The product itself and its products of degradation are not toxic. of Biodegradation Special Remarks on the Not available. Products of Biodegradation Section 13. Disposal Considerations Waste Disposal Waste must be disposed of in accordance with federal, state and local environmental control regulations. Hydroxocobalamin Section 14. Transport Information DOT Classification Not a DOT controlled material (United States). Identification Not applicable. Not applicable. Special Provisions for Transport DOT (Pictograms) Section 15. Other Regulatory Information and Pictograms TSCA 8(b) inventory: Hydroxocobalamin Federal and State Regulations California Proposition 65 Warnings Other Regulations EINECS: This product is on the European Inventory of Existing Commercial Chemical Substances. WHMIS (Canada) Not controlled under WHMIS (Canada). Other Classifications DSCL (EEC) R36/38- Irritating to eyes and skin. S2- Keep out of the reach of children. S46- If swallowed, seek medical advice immediately and show this container or label. Health Hazard HMIS (U.S.A.) 2 National Fire Protection 1 Flammability 1 Association (U.S.A.) Fire Hazard 2 0 Reactivity Health Reactivity 0 Specific hazard Personal Protection E WHMIS (Canada) (Pictograms) DSCL (Europe) (Pictograms) TDG (Canada) (Pictograms) ADR (Europe) (Pictograms) Protective Equipment Hydroxocobalamin Gloves. Lab coat. Dust respirator. Be sure to use an approved/certified respirator or equivalent.
Mechanistic Studies on CysS – A Vitamin B<sub>12</sub>-Dependent Radical SAM Methyltransferase Involved in the Biosynthesis of the <i>tert</i>-Butyl Group of Cystobactamid
作者：Yuanyou Wang、Tadhg P. Begley
DOI：10.1021/jacs.9b06454
日期：2020.6.3
Cobalamin (Cbl)-dependent radicalSAM methyltransferases catalyze methylation reactions at non-nucleophilic centers in a wide range of substrates. CysS is a Cbl-dependent radicalSAM methyltransferase involved in cystobactamid biosynthesis. This enzyme catalyzes the sequential methylation of a methoxy group to form ethoxy, i-propoxy, s-butoxy, and t-butoxy groups on a p-aminobenzoate peptidyl carrier
Fluorophore Assisted Photolysis of Thiolato-Cob(III)alamins
作者：Zachary L. Rodgers、Thomas A. Shell、Alexander M. Brugh、Hannah L. Nowotarski、Malcolm D. E. Forbes、David S. Lawrence
DOI：10.1021/acs.inorgchem.5b02036
日期：2016.3.7
investigated the photolysis of N-acetylcysteinyl cob(III)alamin at several wavelengths within the ultraviolet and visible spectrum. To aid in photolysis, we show that attaching fluorophore “antennae” to the cobalamin scaffold can improve photolytic efficiency by up to an order of magnitude. Additionally, electron paramagnetic resonance confirms previous conjectures that the photolysis of thiolato-cobalamins
已知钴胺素会与硫醇反应，生成稳定的β轴Co III –S键合硫代巯基-钴胺素复合物。但是，与烷基钴胺素中的Co-C键形成鲜明对比的是，硫醇盐-钴胺素中的Co-S键的可光化性仍未确定。我们已经研究了N-乙酰半胱氨酰钴（III）丙氨酸在紫外和可见光谱内的几个波长上的光解作用。为了有助于光解，我们表明将荧光团“天线”连接到钴胺素支架上可以将光解效率提高一个数量级。此外，电子顺磁共振证实了以前的推测，即硫羟钴胺素在长达546 nm的波长处发生光解会产生噻吩基。
Studies on Vitamin B<sub>12</sub> and Related Compounds, 51 [1] Direct Syntheses of Alkylcobalamins from Alkanes and Vitamin B<sub>12r</sub> under "Oxidizing-Reducing" Conditions
作者：Abdussalam Maihub、Hui Bi Xu、Gerhard N. Schrauzer
DOI：10.1515/znb-1980-1122
日期：1980.11.1
n-alkylcobalamins from n-alkanes (C2→C10) and vitamin B12r are described. The compounds are formed under "oxidizing-reducing" conditions: Oxygen radicals (O2-, HOO·, and HO·) are generated from the reaction of O2 with reducing metal ions, notably V+3 (aq) and abstract hydrogen from the alkane substrates. The resulting alkyl radicals are captured by vitamin Bj2r with high efficiency to yield alkylcobalamins
Studies on Vitamin B<sub>12</sub> and Related Compounds, 50 Synthesis of Substituted Alkylcobalamins from Vitamin B<sub>12r</sub> and Radicals Generated from Aldehydes, Alcohols and Ethers under "Oxidizing-Reducing" Conditions. A New Synthesis of Coenzyme B<sub>12</sub> [1]
作者：Gerhard N. Schrauzer、Masao Hashimoto、Abdussalam Maihub
DOI：10.1515/znb-1980-0515
日期：1980.5.1
Organic radicals generated by the oxidation of aldehydes, alcohols and ethers under reducing conditions are trapped by vitamin B12r to yield substituted organocobalamins. From higher n-alkyl aldehydes, acylcobalamins are formed. With acetaldehyde, a mixture of acetylcobalamin and of methylcobalamin is obtained due to the spontaneous decarbonylation of the CH3CO· radical. From saturated alcohols, w
Carboxyalkylcobalamins: Effects of Carboxyl Substituents on Base-on / Base-off Equilibria and Mechanochemical Co–C Bond Cleavage
作者：Gerhard N. Schrauzer、Mary L. Maciejewski-Mattson
DOI：10.1515/znb-2008-0206
日期：2008.2.1
A series of primary and secondary carboxyalkylcobalamins with (CH2)nCOOH groups (n = 1 - 3), CH2-CH(CH3)COOH, CH(R)COOH (R = CH3, C2H5, n-C3H7), CH(CH3)(CH2)nCOOH (n = 1, 2) and CH(COOH)CH2COOH attached to cobalt were synthesized or generated in situ, mostly by the reaction of vitamin B12s or hydridocobalamin with the respective α- or ω-substituted halocarboxylic acids and reactions with olefinic carboxylic
