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- Chromium nicotinate
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Chromium nicotinate | CAS No: 64452-96-6 | GMP-certified suppliers
A medication that supplements intravenous nutrition to maintain chromium levels and prevent deficiency symptoms in patients requiring total parenteral nutrition.
Therapeutic categories
Drugs that are Mainly Renally ExcretedNicotinic Acids
Generic name
Chromium nicotinate
Molecule type
small molecule
CAS number
64452-96-6
DrugBank ID
DB14529
Approval status
Approved drug, Experimental drug
Primary indications
- Indicated for use as a supplement to intravenous solutions given for total parenteral nutrition (TPN), to maintain chromium serum levels and to prevent depletion of endogenous stores and subsequent deficiency symptoms
Product Snapshot
- Chromium nicotinate is available as oral coated and film-coated tablets and tablet kits
- The primary therapeutic use is as a nutritional supplement in total parenteral nutrition to maintain chromium serum levels and prevent deficiency
- It is approved for use in the US market with both approved and experimental indications
Clinical Overview
Chromium nicotinate (CAS number 64452-96-6) is an organic compound classified within the pyridinecarboxylic acids, characterized by a pyridine ring with an attached carboxylic acid group. Clinically, it is indicated as a supplement to intravenous solutions used in total parenteral nutrition (TPN). Its primary purpose in this context is to maintain physiological chromium serum levels and prevent deficiency symptoms arising from depletion of endogenous stores.
Pharmacodynamically, chromium in its trivalent form is an essential component of the glucose tolerance factor, which facilitates insulin-mediated metabolic processes. Chromium enhances insulin binding, increases receptor density, and activates the insulin receptor kinase, collectively improving insulin sensitivity. Deficiency states can manifest with impaired glucose tolerance that normalizes upon intravenous chromium supplementation.
The mechanism of action involves chromium's role as a critical micronutrient in glucose, insulin, and lipid metabolism. It potentiates insulin signaling primarily by modulating effector molecules downstream of the insulin receptor (IR). Activation of the IR leads to autophosphorylation and subsequent phosphorylation of intracellular proteins including phosphatidylinositol 3-kinase (PI3K), which activates Akt kinase. This cascade promotes translocation of glucose transporter-4 (GLUT4) to the cell membrane, facilitating glucose uptake.
Chromium further enhances kinase activity within this pathway and also supports GLUT4 translocation through IR-independent mechanisms, by modulating membrane cholesterol content and regulatory proteins such as sterol regulatory element-binding protein. In addition, chromium attenuates protein tyrosine phosphatase-1B, a negative regulator of insulin signaling, and mitigates endoplasmic reticulum stress that disrupts normal insulin pathways. It also transiently activates AMP-activated protein kinase (AMPK), promoting increased glucose uptake.
Pharmacokinetically, chromium nicotinate is mainly eliminated renally, consistent with its classification among renally excreted agents. Safety data emphasize monitoring to prevent deficiency-related complications without known significant toxicity at nutritional supplementation levels. There are no widely recognized branded products exclusively associated with chromium nicotinate, though it is utilized within parenteral nutrition formulations.
From a pharmaceutical sourcing perspective, procurement of chromium nicotinate as an active pharmaceutical ingredient requires verification of purity, absence of heavy metal contaminants, and compliance with pharmacopoeial standards. Due to its micronutrient nature, ensuring consistent chromium valency and bioavailability is critical. Quality control should focus on robust analytical characterization to support clinical formulation and regulatory submission.
Pharmacodynamically, chromium in its trivalent form is an essential component of the glucose tolerance factor, which facilitates insulin-mediated metabolic processes. Chromium enhances insulin binding, increases receptor density, and activates the insulin receptor kinase, collectively improving insulin sensitivity. Deficiency states can manifest with impaired glucose tolerance that normalizes upon intravenous chromium supplementation.
The mechanism of action involves chromium's role as a critical micronutrient in glucose, insulin, and lipid metabolism. It potentiates insulin signaling primarily by modulating effector molecules downstream of the insulin receptor (IR). Activation of the IR leads to autophosphorylation and subsequent phosphorylation of intracellular proteins including phosphatidylinositol 3-kinase (PI3K), which activates Akt kinase. This cascade promotes translocation of glucose transporter-4 (GLUT4) to the cell membrane, facilitating glucose uptake.
Chromium further enhances kinase activity within this pathway and also supports GLUT4 translocation through IR-independent mechanisms, by modulating membrane cholesterol content and regulatory proteins such as sterol regulatory element-binding protein. In addition, chromium attenuates protein tyrosine phosphatase-1B, a negative regulator of insulin signaling, and mitigates endoplasmic reticulum stress that disrupts normal insulin pathways. It also transiently activates AMP-activated protein kinase (AMPK), promoting increased glucose uptake.
Pharmacokinetically, chromium nicotinate is mainly eliminated renally, consistent with its classification among renally excreted agents. Safety data emphasize monitoring to prevent deficiency-related complications without known significant toxicity at nutritional supplementation levels. There are no widely recognized branded products exclusively associated with chromium nicotinate, though it is utilized within parenteral nutrition formulations.
From a pharmaceutical sourcing perspective, procurement of chromium nicotinate as an active pharmaceutical ingredient requires verification of purity, absence of heavy metal contaminants, and compliance with pharmacopoeial standards. Due to its micronutrient nature, ensuring consistent chromium valency and bioavailability is critical. Quality control should focus on robust analytical characterization to support clinical formulation and regulatory submission.
Identification & chemistry
| Generic name | Chromium nicotinate |
|---|---|
| Molecule type | Small molecule |
| CAS | 64452-96-6 |
| UNII | A150AY412V |
| DrugBank ID | DB14529 |
Pharmacology
| Summary | Chromium is an essential trace element that modulates glucose metabolism by enhancing insulin receptor β-subunit kinase activity and downstream signaling pathways, including PI3K and Akt, promoting GLUT4 translocation and glucose uptake. It also facilitates insulin-independent GLUT4 translocation through membrane cholesterol modulation and reduces negative regulators of insulin signaling such as PTP-1B and ER stress-associated pathways. Chromium supplementation supports maintenance of insulin sensitivity and normal glucose homeostasis, particularly in parenteral nutrition settings. |
|---|---|
| Mechanism of action | Chromium is an essential nutrient involved in the metabolism of glucose, insulin and blood lipids. Its role in potentiating insulin signalling cascades has been implicated in several studies. Chromium upregulates insulin-stimulated insulin signal transduction via affecting effector molecules downstream of the insulin receptor (IR). IR-mediated signalling pathway involves phoshorylation of multiple intracellular domains and protein kinases, and downstream effector molecules . Upon activation by ligands, intracellular β-subunit of IR autophosphorylates and activates tyrosine kinase domain of the IR, followed by activation and phosphorylation of regulatory proteins and downstream signalling effectors including phosphatidylinositol 2-kinase (PI3K). PI3K activates further downstream reaction cascades to activate protein kinase B (Akt) to ultimately promote translocation of glucose transporter-4 (Glut4)-vesicles from the cytoplasm to the cell surface and regulate glucose uptake . Chromium enhances the kinase activity of insulin receptor β and increases the activity of downstream effectors, pI3-kinase and Akt. Under insulin-resistant conditions, chromium also promotes GLUT-4 transporter translocation that is independent of activity of IR, IRS-1, PI3-kinase, or Akt; chromium mediates cholesterol efflux from the membranes via increasing fluidity of the membrane by decreasing the membrane cholesterol and upregulation of sterol regulatory element-binding protein . As a result, intracellular GLUT-4 transporters are stimulated to translocate from intracellular to the plasma membrane, leading to enhanced glucose uptake in muscle cells . Chromium attenuates the activity of PTP-1B _in vitro,_ which is a negative regulator of insulin signaling. It also alleviates ER stress that is observed to be elevated the suppression of insulin signaling. ER stress is thought to activate c-Jun N-terminal kinase (JNK), which subsequently induces serine phosphorylation of IRS and aberration of insulin signalling . Transient upregulation of AMPK by chromium also leads to increased glucose uptake . |
| Pharmacodynamics | Trivalent chromium is part of glucose tolerance factor, an essential activator of insulin-mediated reactions. Chromium helps to maintain normal glucose metabolism and peripheral nerve function. Chromium increases insulin binding to cells, increases insulin receptor density and activates insulin receptor kinase leading to enhanced insulin sensitivity . In chromium deficiency, intravenous administration of chromium resulted in normalization of the glucose tolerance curve from the diabetic-like curve typical of chromium deficiency. |
Targets
| Target | Organism | Actions |
|---|---|---|
| Cytochrome b5 | Humans |
ADME / PK
| Absorption | Chromium compounds are both absorbed by the lung and the gastrointestinal tract. Oral absorption of chromium compounds in humans can range between 0.5% and 10%, with the hexavalent (VI) chromium more easily absorbed than the trivalent (III) form . Absorption of chromium from the intestinal tract is low, ranging from less than 0.4% to 2.5% of the amount consumed . Vitamin C and the vitamin B niacin is reported to enhance chromium absorption . Most hexavalent Cr (VI) undergoes partial intragastric reduction to Cr (III) upon absorption, which is an action mainly mediated by sulfhydryl groups of amino acids . Cr (VI) readily penetrates cell membranes and chromium can be found in both erythrocytes and plasma after gastrointestinal absorption of Cr (IV). In comparison, the presence of chromium is limited to the plasma as Cr (III) displays poor cell membrane penetration . Once transported through the cell membrane, Cr (VI) is rapidly reduced to Cr (III), which subsequently binds to macromolecules or conjugate with proteins. Cr (III) may be bound to transferrin or other plasma proteins, or as complexes, such as glucose tolerance factor (GTF). |
|---|---|
| Half-life | The elimination half-life of hexavalent chromium is 15 to 41 hours . |
| Protein binding | In the blood, 95% of chromium (III) is bound to large molecular mass proteins, such as transferrin, while a small proportion associates with low molecular mass oligopeptides . Serum chromium is bound to transferrin in the beta globulin fraction. |
| Metabolism | The metabolism of Cr (VI) involves reduction by small molecules and enzyme systems to generate Cr (III) and reactive intermediates. During this process, free radicals can be generated, which is thought to induce damage of cellular components and cause toxicity of chromium . The metabolites bind to cellular constituents . |
| Route of elimination | Absorbed chromium is excreted mainly in the urine, accounting for 80% of total excretion of chromium; small amounts are lost in hair, perspiration and bile . Chromium is excreted primarily in the urine by glomerular filtration or bound to a low molecular-weight organic transporter . |
| Volume of distribution | Absorbed chromium is distributed to all tissues of the body and its distribution in the body depends on the species, age, and chemical form . Circulating Cr (III) following oral or parenteral administration of different compounds can be taken up by tissues and accumulates in the liver, kidney, spleen, soft tissue, and bone . |
| Clearance | Excretion of chromium is via the kidneys ranges from 3 to 50 μg/day. The 24-hour urinary excretion rates for normal human subjects are reported to be 0.22 μg/day . |
Formulation & handling
- Chromium nicotinate is formulated for oral administration primarily as coated and film-coated tablets.
- This small molecule's low water solubility suggests formulation strategies that enhance bioavailability may be required.
- Co-administration with vitamin C and niacin-containing foods or supplements can improve chromium absorption, indicating potential food interaction considerations.
Regulatory status
| Lifecycle | The active pharmaceutical ingredient is approaching patent expiry in the US, transitioning the market toward increased generic competition and greater product availability. This stage reflects a move from exclusive brand presence to broader market access. |
|---|
| Markets | US |
|---|
Supply Chain
| Supply chain summary | The manufacturing and supply landscape for chromium nicotinate in the US includes several originator companies producing branded products such as Adelgadina, Dayavite, and Foliflex. These branded formulations have a presence primarily in the US market, with little indication of availability in the EU or other regions. Patent expiry status is not specified, limiting assessment of upcoming or existing generic competition. |
|---|
Safety
| Toxicity | Oral LD50 for Cr (VI) is 135 - 175 mg/kg in mouse and 46 - 113 mg/kg in rat . Oral LD50 for Cr (III) in rat is >2000 mg/kg . LD50 of chromium (III) oxide in rats is reported to be > 5g/kg . Other LD50 values reported for rats include: 3.5 g/kg (CI 3.19-3.79 g/kg) for chromium sulphate; 11.3 g/kg for chromium (III) acetate; 3.3 g/kg for chromium nitrate; and 1.5 g/kg for chromium nitrate nonahydrate . Acute overdose of chromium is rare and seriously detrimental effects of hexavalent chromium are primarily the result of chronic low-level exposure . In case of overdose with minimal toxicity following acute ingestion, treatment should be symptomatic and supportive . There is no known antidote for chromium toxicity. Hexavalent chromium is a Class A carcinogen by the inhalation route of exposure and Class D by the oral route . The oral lethal dose in humans has been estimated to be 1-3 g of Cr (VI); oral toxicity most likely involves gastrointestinal bleeding rather than systemic toxicity . Chronic exposure may cause damage to the following organs: kidneys, lungs, liver, upper respiratory tract [MSDS]. Soluble chromium VI compounds are human carcinogens. Hexavalent chromium compounds were mutagenic in bacteria assays and caused chromosome aberrations in mammalian cells. There have been associations of increased frequencies of chromosome aberrations in lymphocytes from chromate production workers . In human cells _in vitro_, Cr (VI) caused chromosomal aberrations, sister chromatid exchanges and oxidative DNA damage . |
|---|
High Level Warnings:
- Hexavalent chromium compounds are classified as Class A carcinogens via inhalation and exhibit mutagenic and genotoxic effects in mammalian cells
- Acute oral toxicity varies by chromium form
- Cr (VI) exhibits significantly lower LD50 values compared to Cr (III) forms, indicating higher acute toxicity
Chromium nicotinate is a type of Antimetabolites
Antimetabolites are a prominent category of pharmaceutical active pharmaceutical ingredients (APIs) utilized in the treatment of various diseases, particularly cancer. These compounds are structurally similar to naturally occurring metabolites essential for cellular processes such as DNA and RNA synthesis. By mimicking these metabolites, antimetabolites interfere with the normal functioning of cellular pathways, leading to inhibition of cancer cell growth and proliferation.
One of the widely used antimetabolites is methotrexate, a folic acid antagonist that inhibits the enzyme dihydrofolate reductase, disrupting the production of DNA and RNA. This disruption impedes the growth of rapidly dividing cancer cells. Another common antimetabolite is 5-fluorouracil (5-FU), which inhibits the enzyme thymidylate synthase, thereby interfering with DNA synthesis and inhibiting cancer cell proliferation.
Antimetabolites can be classified into several subcategories based on their mechanism of action and chemical structure. These include purine and pyrimidine analogs, folic acid antagonists, and pyrimidine synthesis inhibitors. Examples of antimetabolites in these subcategories include azathioprine, cytarabine, and gemcitabine.
Despite their effectiveness, antimetabolites can exhibit certain side effects due to their interference with normal cellular processes. These side effects may include gastrointestinal disturbances, myelosuppression (reduced production of blood cells), and hepatotoxicity.
In conclusion, antimetabolites are a vital category of pharmaceutical APIs used in the treatment of various diseases, especially cancer. By mimicking natural metabolites and disrupting crucial cellular processes, these compounds effectively inhibit cancer cell growth and proliferation. However, their usage should be carefully monitored due to potential side effects.
