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General Description:

Chromium, identified by CAS number 7440-47-3, is a notable compound with significant therapeutic applications. Chromium is a transition element with the chemical symbol Cr and atomic number 24 that belongs to Group 6 of the periodic table. It is used in various chemical, industrial and manufacturing applications such as wood preservation and metallurgy. The uses of chromium compounds depend on the valency of chromium, where trivalent Cr (III) compounds are used for dietary Cr supplementation and hexavalent Cr (VI) compounds are used as corrosion inhibitors in commercial settings and are known to be human carcinogens . Humans can be exposed to chromium via ingestion, inhalation, and dermal or ocular exposure . Trivalent chromium (Cr(III)) ion is considered to be an essential dietary trace element as it is involved in metabolism of blood glucose, regulation of insulin resistance and metabolism of lipids. Clinical trials and other studies suggest the evidence of chromium intake improving glucose tolerance in patients with Type I and II diabetes, however its clinical application in the standard management of type II diabetes mellitus is not established. Chromium deficiency has been associated with a diabetic-like state, impaired growth, decreased fertility and increased risk of cardiovascular diseases . According to the National Institute of Health, the daily dietary reference intake (DRI) of chromium for adult male and non-pregnant female are 35 μg and 25 μg, respectively . Chromium picolinate capsules may be used as nutritional adjuvant in patients with or at risk of type 2 diabetes mellitus (T2DM) to improve blood sugar metabolism and stabilize the levels of serum cholesterol. Chromium chloride is available as an intravenous injection for use as a supplement to intravenous solutions given for total parenteral nutrition (TPN) .

Indications:

This drug is primarily indicated for: 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 . Its use in specific medical scenarios underscores its importance in the therapeutic landscape.

Metabolism:

Chromium undergoes metabolic processing primarily in: 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 . This metabolic pathway ensures efficient processing of the drug, helping to minimize potential toxicity and side effects.

Absorption:

The absorption characteristics of Chromium are crucial for its therapeutic efficacy: 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). The drug's ability to rapidly penetrate into cells ensures quick onset of action.

Half-life:

The half-life of Chromium is an important consideration for its dosing schedule: The elimination half-life of hexavalent chromium is 15 to 41 hours . This determines the duration of action and helps in formulating effective dosing regimens.

Protein Binding:

Chromium exhibits a strong affinity for binding with plasma proteins: 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 . This property plays a key role in the drug's pharmacokinetics and distribution within the body.

Route of Elimination:

The elimination of Chromium from the body primarily occurs through: 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 . Understanding this pathway is essential for assessing potential drug accumulation and toxicity risks.

Volume of Distribution:

Chromium is distributed throughout the body with a volume of distribution of: 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 . This metric indicates how extensively the drug permeates into body tissues.

Clearance:

The clearance rate of Chromium is a critical factor in determining its safe and effective dosage: 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 . It reflects the efficiency with which the drug is removed from the systemic circulation.

Pharmacodynamics:

Chromium exerts its therapeutic effects through: 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 . The drug's ability to modulate various physiological processes underscores its efficacy in treating specific conditions.

Mechanism of Action:

Chromium functions by: 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 . This mechanism highlights the drug's role in inhibiting or promoting specific biological pathways, contributing to its therapeutic effects.

Toxicity:

Classification:

Chromium belongs to the class of inorganic compounds known as homogeneous transition metal compounds. These are inorganic compounds containing only metal atoms,with the largest atom being a transition metal atom, classified under the direct parent group Homogeneous transition metal compounds. This compound is a part of the Inorganic compounds, falling under the Homogeneous metal compounds superclass, and categorized within the Homogeneous transition metal compounds class, specifically within the None subclass.

Categories:

Chromium is categorized under the following therapeutic classes: Cell-mediated Immunity, Diet, Food, and Nutrition, Drugs that are Mainly Renally Excreted, Elements, Food, Increased Histamine Release, Metals, Metals, Heavy, Micronutrients, Minerals, Physiological Phenomena, Standardized Chemical Allergen, Trace Elements, Transition Elements. These classifications highlight the drug's diverse therapeutic applications and its importance in treating various conditions.

Experimental Properties:

Further physical and chemical characteristics of Chromium include:

• Water Solubility: Insoluble
• Melting Point: 1900
• Boiling Point: 2642