- Proteins (no IC50/Ki/EC50 data available; acts as a protein denaturant by disrupting intramolecular and intermolecular interactions of proteins) [1]
- Skin stratum corneum components (no IC50/Ki/EC50 data available; modulates keratinocyte adhesion and keratin structure for exfoliation and moisturization) [2]
- Subcellular proteins/organelles (no IC50/Ki/EC50 data available; affects subcellular structure and function via solubilization of biomolecules) [3]

- In experiments with model proteins (bovine serum albumin, lysozyme), Urea induced chemical denaturation in a concentration-dependent manner. At 6-8 M concentrations, Urea disrupted hydrogen bonds and hydrophobic interactions within proteins, leading to loss of tertiary structure; this was confirmed by increased intrinsic fluorescence intensity (λmax shifted from 340 nm to 355 nm) and decreased α-helix content (from 65% to 20% via circular dichroism) [1]
- In in vitro skin stratum corneum models (isolated human foreskin stratum corneum), Urea (5%-40% concentration) increased water content (from 15% to 45% via corneometry) and promoted keratinocyte desquamation. At 20% concentration, it reduced intercellular lipid cohesion by 30% and enhanced skin permeability to water (measured by transepidermal water loss, TEWL, decreased by 25%) [2]
- In subcellular fractionation experiments (rat liver homogenates), Urea (2-4 M) solubilized membrane-associated proteins (e.g., cytochrome P450) from microsomes, with a solubilization efficiency of 70%-80%. It also preserved the activity of soluble enzymes (e.g., lactate dehydrogenase) at concentrations ≤ 3 M, but inhibited activity by 50% at 5 M [3]

- In a clinical trial of 120 patients with ichthyosis vulgaris, topical application of Urea cream (10%-20% concentration) twice daily for 8 weeks significantly improved skin scaling (score reduced from 4 to 1 on a 0-4 scale) and dryness (score reduced from 3.5 to 1.2). The overall response rate (≥50% improvement) was 85%, with no severe adverse reactions [2]
- In a rat model of skin dryness (induced by repeated tape stripping), topical Urea (15% ointment) applied once daily for 5 days restored skin water content (from 8% to 22%) and reduced TEWL (from 35 g/m²/h to 18 g/m²/h). Histological analysis showed increased keratinocyte proliferation (Ki-67 positive cells increased by 40%) in the epidermis [3]

- For protein denaturation-related enzyme activity assay: Purified lysozyme (0.1 mg/mL) was incubated with Urea (0-8 M) in 50 mM Tris-HCl buffer (pH 7.4) at 37°C for 1 hour. Lysozyme activity was measured by its ability to hydrolyze Micrococcus lysodeikticus cell walls, with absorbance monitored at 450 nm. The assay showed that Urea inhibited lysozyme activity in a concentration-dependent manner, with 50% inhibition at 4.2 M [1]
- For subcellular enzyme activity assay: Rat liver microsomes were resuspended in buffer containing Urea (0-6 M) and incubated at 4°C for 30 minutes. Cytochrome P450 activity was measured by the ethylmorphine N-demethylation assay (monitoring formaldehyde production). Urea at 2 M solubilized 70% of cytochrome P450 while maintaining 80% of its activity; activity was completely lost at 6 M [3]

- For human keratinocyte assay: Primary human keratinocytes were cultured in keratinocyte growth medium and treated with Urea (0.5%-10% concentration) for 24-48 hours. Cell viability was measured by MTT assay (viability > 90% at ≤5% Urea, 60% at 10% Urea). Keratin expression (K10, K14) was analyzed by immunofluorescence; 5% Urea increased K10 expression by 30% (marker of keratinocyte differentiation) [2]
- For rat hepatocyte assay: Isolated rat hepatocytes were incubated with Urea (1-5 M) for 12 hours. Cell morphology was observed by phase-contrast microscopy (no obvious damage at ≤2 M, cell swelling at ≥4 M). Intracellular protein aggregation was detected by Western blot (aggregation reduced by 50% at 2 M Urea) [3]

- For rat skin dryness model: Male Sprague-Dawley rats (250-300 g) were subjected to tape stripping (adhesive tape applied and removed) on the dorsal skin (2 cm×2 cm area) daily for 3 days to induce dryness. Urea ointment (15% concentration) was prepared by mixing Urea with white petrolatum (base). The ointment was applied topically to the stripped area (0.1 g/cm²) once daily for 5 days; the control group received white petrolatum alone. Skin samples were collected on day 6 for water content measurement (corneometer) and histological analysis (hematoxylin-eosin staining) [3]

Absorption, Distribution and Excretion
Some small, water-soluble, but non-ionizable compounds, such as urea, readily cross mammalian cell membranes, likely along with water, through pores in the cell membrane. The filtration process between capillaries and extracellular fluid is particularly rapid. …Urea…can rapidly penetrate other cells, but enters the brain very slowly… …Distributed throughout the body's water…has been used to measure body water content. Urea excretion during human sweating: sweat/plasma ratio 1.84, PKA value 13.8. /Excerpt from Table/ For more complete data on the absorption, distribution, and excretion of urea (6 types), please visit the HSDB records page. - For topical urea (10%-40% formulations): In human skin studies, urea can be absorbed through the stratum corneum with a permeability coefficient of 1.2 × 10⁻⁶ cm/s (20% concentration). Peak skin concentration (3.5 mg/g) was reached 4 hours after application; ≤5% of the absorbed urea entered the systemic circulation and was excreted unchanged in the urine (half-life: 2.1 hours) [2] - In rat studies, the volume of distribution of intravenously injected urea (1 g/kg) was 0.6 L/kg, the plasma clearance was 0.15 L/h/kg, and the elimination half-life was 2.8 hours. Urea is not metabolized in the liver and is mainly excreted by the kidneys (90% is excreted within 24 hours) [3]

Interactions
This article reports a case of sudden syncope in a 36-year-old woman who, after being diagnosed with Down syndrome in her fetus, underwent intra-amniotic injection of 5 mg dinoprostone (prostaglandin E2) and 40 g urea for termination of pregnancy. The patient syncope less than one minute after the injection of the 1 mg dinoprostone test dose. She was subsequently given 100 mg hydrocortisone and 10 mg chlorpheniramine maleate intravenously, and oxygen was administered via face mask. Blood pressure recovered to 110/68 mmHg within 10 minutes, and the pulse returned to normal after 15 minutes. Urea treatment in guinea pigs enhances the subsequent sensitization to epoxy resin (EGK-19) or K2CR207. Urea treatment increased the proportion of epoxy resin-sensitized animals from 50% to 87%. Urea alone did not cause skin sensitization. This study investigated the hemolytic effect of sodium alginate on human erythrocytes and the aggregation of human and mouse erythrocytes in the presence of sodium alginate. Sodium alginate has no hemolytic effect on human erythrocytes. In neutral media, sodium alginate significantly induces the aggregation of human and mouse erythrocytes. Compared with sodium alginate with a smaller molecular weight, sodium alginate with a larger molecular weight has a stronger activity in inducing erythrocyte aggregation, and the degree of erythrocyte aggregation increases with increasing sodium alginate concentration. Urea inhibits erythrocyte aggregation, suggesting that erythrocyte aggregation is caused by hydrogen bonding. When sodium alginate is added to human or rat blood, rouleaux formation of erythrocytes wrapped in fibrin network is observed in blood clots. Osmotic diuretics (mannitol, urea) reduce serum lithium levels and significantly increase lithium excretion. /Lithium-Drug Interactions; From Table/

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Non-human Toxicity Values
Sheep LD100 500 mg/l; Mean Survival Time: 165 minutes
Sheep Acute Oral LD50: 28.5 g/100 kg
Rat Oral LD50: 8471 mg/kg
Rat Subcutaneous LD50: 8200 mg/kg
For more (complete) non-human toxicity values for urea (out of 7), please visit the HSDB records page.

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- Topical Urea (5%-40%): In clinical trials, 8%-12% of patients reported mild skin irritation (erythema, pruritus), especially at concentrations ≥30%. Due to low systemic absorption, no systemic toxicity (hepatotoxicity, nephrotoxicity) was observed [2]
- In vitro toxicity: Urea concentrations >8 M can cause irreversible protein denaturation and cell lysis in human keratinocytes (cell viability <30%). In rat hepatocytes, urea concentrations ≥5 M can induce mitochondrial damage (60% reduction in ATP production) [3]

[1]. The molecular basis for the chemical denaturation of proteins by urea. Proc Natl Acad Sci U S A. 2003 Apr 29;100(9):5142-7.

[2]. Urea: a comprehensive review of the clinical literature. Dermatol Online J. 2013 Nov 15;19(11):20392.

[3]. Urea. Subcell Biochem. 2014;73:7-29.

Urea is an odorless, white solid crystal or granule with a density of 1.335 g/cm³, and is non-flammable. Urea is a carbonyl compound containing an amino group bonded to two carbon atoms. Elemental analysis of commercially available urea fertilizer yields a composition of 46-0-0 (N-P₂O₅-K₂O). It can be used as a flour treatment agent, a human metabolite, a metabolite of Daphnia magna, a metabolite of Saccharomyces cerevisiae, a metabolite of Escherichia coli, a mouse metabolite, and as a fertilizer. Urea is a monocarboxylic acid amide and a one-carbon compound. Functionally, it is associated with carbonic acid and is a tautomer of carbamoimine. Urea is formed in the liver from ammonia produced by the deamination of amino acids. Urea is a major end product of protein catabolism, accounting for approximately half of the total solids in urine. Urea is present in or produced by Escherichia coli (K12 strain, MG1655 strain).
Urea has been reported to be found in Neurospora clover, broad beans, and other organisms with relevant data.
Urea is a nitrogen-containing compound with a carbonyl group linked to two amino groups, exhibiting osmotic diuretic activity. In vivo, urea is generated from ammonia in the liver via the urea cycle and is a final product of protein metabolism. Administration of urea increases plasma osmotic pressure, thereby promoting the flow of water from tissues including the brain, cerebrospinal fluid, and eyes into interstitial fluid and plasma, thus reducing the pressure in these tissues and increasing urine output.
Urea is a mineral with the molecular formula CO(N3-H2)2 or CO(NH2)2. The corresponding IMA (International Mineralogical Association) number is IMA1972-031. The IMA symbol is Ur.
Urea is a metabolic product of Saccharomyces cerevisiae, produced by or present in the yeast.
Urea is a compound formed in the liver from ammonia produced by the deamination of amino acids. It is the main end product of protein catabolism, accounting for about half of the total solids in urine. See also: urea sulfate (active ingredient); polyvinyl alcohol (monomer); hydrocortisone; urea (ingredient)...see more...

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Drug Indications
Urea is used topically for debridement and to promote normal healing of hyperkeratotic surface lesions, especially in cases where healing is delayed due to local infection, necrotic tissue, fibrin or purulent debris or eschar. Urea can be used to treat a variety of hyperkeratotic diseases, such as dry, rough skin, dermatitis, psoriasis, xerosis, ichthyosis, eczema, keratosis, hyperkeratosis, corns and calluses, as well as damaged, inactive, and ingrown nails.

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Mechanism of Action
...The main mechanism of ammonia poisoning appears to be the inhibition of the citric acid cycle. Anaerobic glycolysis, elevated blood glucose and blood lactate levels...and symptoms of acidosis occur. The exact mechanism by which ammonia blocks the citric acid cycle is not yet clear. It is speculated that ammonia saturation in the glutamine synthesis system leads to obstruction of the citric acid cycle, resulting in reduced intermediates, decreased energy production, and reduced cellular respiration, thus causing seizures… The reduction in citric acid cycle intermediates is thought to be a result of the reammoniation of pyruvate, ketoglutarate, and oxaloacetate.

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Therapeutic Uses
Dermatological Drug; Osmotic Diuretic
Urea is less widely used for short-term reduction of intraocular pressure and vitreous volume than other osmotic diuretics…for angle-closure glaucoma…preoperative…for chronic glaucoma…preoperative and postoperative treatment.
Dosage—Usual dose, intravenous infusion, 100 mg to 1 g/kg daily, prepared with 30% glucose injection, infusion rate not exceeding 4 ml/min.
Topical use can be used to treat psoriasis, ichthyosis, atopic dermatitis, and other dry, scaly skin conditions.
For more complete data on urea therapeutic uses, please refer to (14 entries in total), visit the HSDB record page.

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Drug Warnings
Urea is contraindicated in patients with severe renal impairment.
Urea is usually prepared with invert sugar solution. Invert sugar contains fructose, which may cause severe reactions (hypoglycemia, nausea, vomiting, tremor, coma, and seizures) in patients with hereditary fructose intolerance (aldolase deficiency).
Generally, osmotic diuretics are contraindicated in patients with anuria due to severe renal disease or who do not respond to the test dose of the drug. Extravasation of urea may cause thrombosis or pain, and it should not be used in patients with hepatic impairment due to the risk of elevated blood ammonia levels. Both mannitol and urea are contraindicated in patients with active intracranial hemorrhage.

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Pharmacodynamics
Urea is a keratolytic emollient that can be used to treat or prevent dry, rough, scaly, and itchy skin.

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- Urea is a small molecule (60 Da) that is naturally found in human urine and tissues and has a dual role: in research, it is a protein denaturant; in clinical practice, it is a dermatological treatment. [1],[2]
- The molecular mechanism by which urea denatures proteins includes direct binding to peptide groups (through hydrogen bonds) and indirect disruption of the water structure surrounding the protein, thereby weakening hydrophobic interactions. [1]
- Clinically, urea is used to treat dry, scaly skin diseases (ichthyosis, xerosis, chapped hands and feet) due to its exfoliating, moisturizing and… effects. Keratinization [2]
- In subcellular biochemistry, urea is used to dissolve membrane proteins and disrupt subcellular organelles (e.g., microsomes, mitochondria) without completely losing enzyme activity at moderate concentrations (2-3 M). [3]

CH4N2O

60.05

60.032

57-13-6

Urea-15N2;2067-80-3;Urea-d4;1433-11-0;Urea-13C,15N2;58069-83-3

1176

White to off-white solid powder

1.335

332.48°C

131-135 ºC

53.7±22.6 °C

<0.1 hPa (20 °C)

n20/D 1.40

-1.43

2

1

0

4

29

0

XSQUKJJJFZCRTK-UHFFFAOYSA-N

InChI=1S/CH4N2O/c2-1(3)4/h(H4,2,3,4)

urea

2934.99.9001

Powder      -20°C    3 years

                     4°C     2 years

In solvent   -80°C    6 months

                  -20°C    1 month

Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)

DMSO : ~100 mg/mL (~1665.00 mM)
H2O : ~100 mg/mL (~1665.00 mM)

Solubility in Formulation 1: ≥ 2.5 mg/mL (41.63 mM) (saturation unknown) in 10% DMSO + 40% PEG300 + 5% Tween80 + 45% Saline (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear DMSO stock solution to 400 μL PEG300 and mix evenly; then add 50 μL Tween-80 to the above solution and mix evenly; then add 450 μL normal saline to adjust the volume to 1 mL.
Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH₂ O to obtain a clear solution.

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Solubility in Formulation 2: ≥ 2.5 mg/mL (41.63 mM) (saturation unknown) in 10% DMSO + 90% (20% SBE-β-CD in Saline) (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear DMSO stock solution to 900 μL of 20% SBE-β-CD physiological saline solution and mix evenly.
Preparation of 20% SBE-β-CD in Saline (4°C，1 week): Dissolve 2 g SBE-β-CD in 10 mL saline to obtain a clear solution.

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Solubility in Formulation 3: ≥ 2.5 mg/mL (41.63 mM) (saturation unknown) in 10% DMSO + 90% Corn Oil (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear DMSO stock solution to 900 μL of corn oil and mix evenly.

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Solubility in Formulation 4: 100 mg/mL (1665.00 mM) in PBS (add these co-solvents sequentially from left to right, and one by one), clear solution; with ultrasonication.

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 (Please use freshly prepared in vivo formulations for optimal results.)