Glucocorticoid receptor

Human vasoconstrictor assay: Hydrocortisone buteprate 0.1% cream showed significantly higher vasoconstrictive effect (mean score 1.8) vs. hydrocortisone 1% (mean score 0.5) and hydrocortisone butyrate 0.1% (mean score 1.2) after 6h occlusion (p<0.01). Maximal blanching at 24h post-application.[1]
Clinical efficacy: In atopic dermatitis patients, hydrocortisone buteprate 0.1% cream applied twice daily for 21 days reduced EASI score by 78.3% (vs. 52.7% for vehicle, p<0.001). Pruritus VAS decreased from 7.2 to 1.4.[1]

Absorption, Distribution and Excretion
Topical corticosteroids are absorbed through normal, intact skin. Skin inflammation and/or other disease processes increase percutaneous absorption. Corticosteroids are primarily metabolized in the liver and then excreted by the kidneys. Some topical corticosteroids and their metabolites are also excreted via bile. Metabolism/Metabolites Metabolized primarily by CYP3A4 in the liver. Biological Half-Life 6–8 hours. Rapidly hydrolyzed in human skin to the active metabolite 17-butyrate hydrocortisone (tₘₐₓ = 4 hours). Low systemic absorption: After daily use of 40 g, plasma concentration Cₘₐₓ < 1 ng/mL. Metabolized by hepatic CYP3A4 to cortisone derivatives. [1]

No hypothalamic-pituitary-adrenal axis suppression was observed (plasma cortisol >140 nmol/L after 4 weeks of treatment). Local side effects: mild skin atrophy (2 out of 120 patients), telangiectasia (1 out of 120 patients). Treatment index (TI) = 12.5 (calculated as ED₅₀ efficacy / ED₅₀ skin atrophy). [1]
Protein binding
95% 636398 Rats Oral LD50 5120 mg/kg Sensory organs and special senses: ptosis; Behavior: altered motor activity (specific test); Lung, pleural cavity or respiration: respiratory depression, Journal of Toxicological Science, 6 (Supplement)
636398 Rats Intraperitoneal LD50 1420 mg/kg Sensory organs and special senses: ptosis; Behavior: altered motor activity (specific test); Lung, pleural cavity or respiration: respiratory depression, Journal of Toxicological Science, 6 (Supplement)
636398 Rats Subcutaneous LD50 3260 mg/kg Sensory organs and special senses: ptosis; Behavior: altered motor activity (specific test); Lung, pleural cavity or respiration: respiratory depression and depression, Journal of Toxicological Science, 6 (Supplement)
636398 Mice Oral LD50 6720 mg/kg Sensory organs and special senses: ptosis; Behavior: altered motor activity (specific test); Lungs, pleura, or respiration: respiratory depression, Journal of Toxicological Science, 6(Supplement)
636398 Intraperitoneal LD50 in mice: 1660 mg/kg Sensory organs and special senses: ptosis; Behavior: altered motor activity (specific test); Lungs, pleura, or respiration: respiratory depression, Journal of Toxicological Science, 6(Supplement)

Hydrocortisone propionate butyrate is a corticosteroid hormone and also a butyrate ester. Hydrocortisone propionate butyrate is the propionate form of hydrocortisone and is a synthetic glucocorticoid receptor agonist with anti-inflammatory, antipruritic, and vasoconstrictive effects. Binding and activation of glucocorticoid receptors leads to the activation of lipocorticin, which in turn inhibits cytosolic phospholipase A2. Deficiency of phospholipase A2 prevents the release of arachidonic acid (a precursor to the inflammatory mediators prostaglandins and leukotrienes) from the cell membrane. Secondly, mitogen-activated protein kinase 1 (MAPK) phosphatase 1 is induced, resulting in dephosphorylation and inactivation of the Jun N-terminal kinase, directly inhibiting c-Jun-mediated transcription. Finally, the transcriptional activity of nuclear factor (NF)-κB is blocked, thereby inhibiting the transcription of cyclooxygenase 2, which is essential for prostaglandin production. Pharmaceutical Indications: For the relief of inflammatory and pruritus symptoms in corticosteroid-responsive dermatitis. It is also used to treat endocrine (hormonal) disorders (adrenal insufficiency, Addison's disease). In addition, it is used to treat a variety of immune and allergic diseases, such as arthritis, lupus, severe psoriasis, severe asthma, ulcerative colitis, and Crohn's disease.

---

Mechanism of Action
Hydrocortisone binds to cytoplasmic glucocorticoid receptors. After the newly formed receptor-ligand complex binds to the receptor, it translocates to the cell nucleus and binds to multiple glucocorticoid response elements (GREs) in the promoter regions of target genes. Subsequently, the DNA-bound receptor interacts with basal transcription factors, leading to increased expression of specific target genes. The anti-inflammatory effect of glucocorticoids is thought to be related to lipocortin, a protein that inhibits phospholipase A2, which controls the biosynthesis of prostaglandins and leukotrienes by inhibiting arachidonic acid. Specifically, glucocorticoids induce the synthesis of lipocortin-1 (annexin-1), which then binds to the cell membrane, preventing phospholipase A2 from contacting its substrate arachidonic acid. This leads to a decrease in the production of arachidic acid. The expression of cyclooxygenases (COX-1 and COX-2) is also inhibited, thereby enhancing the above effects. In other words, the two main products of inflammation—prostaglandins and leukotrienes—are inhibited by glucocorticoids. Glucocorticoids can also stimulate lipocortin-1 to escape into the extracellular space, where it binds to leukocyte membrane receptors, inhibiting various inflammatory responses: epithelial cell adhesion, migration, chemotaxis, phagocytosis, respiratory burst, and the release of various inflammatory mediators (lysosomal enzymes, cytokines, tissue plasminogen activator, chemokines, etc.) from neutrophils, macrophages, and mast cells. Furthermore, corticosteroids suppress the immune system through mechanisms including decreased lymphatic system function, reduced immunoglobulin and complement concentrations, lymphopenia, and interference with antigen-antibody binding.

---

Pharmacodynamics
Hydrocortisone is the most important glucocorticoid in the human body. It is essential for life and regulates or supports many important cardiovascular, metabolic, immune, and homeostatic functions.
Topical application of hydrocortisone utilizes its anti-inflammatory or immunosuppressive properties to treat inflammation caused by corticosteroid-sensitive dermatitis. Glucocorticoids are a class of steroid hormones characterized by their ability to bind to cortisol receptors and trigger a variety of important cardiovascular, metabolic, immune, and homeostatic effects. Glucocorticoids differ from mineralocorticoids and sex hormones in that they have different receptors, target cells, and mechanisms of action. Strictly speaking, the term "corticosteroid" refers to both glucocorticoids and mineralocorticoids, but it is often used synonymously with glucocorticoids. Glucocorticoids suppress cell-mediated immune responses. They function by inhibiting genes encoding cytokines IL-1, IL-2, IL-3, IL-4, IL-5, IL-6, IL-8, and TNF-α, with IL-2 being the most important. Reduced cytokine production limits T cell proliferation. Glucocorticoids also suppress humoral immunity, leading to a decrease in the amount of IL-2 and its receptor expressed by B cells. This reduces B cell clonal expansion and antibody synthesis. Decreased IL-2 levels also lead to a reduction in activated T lymphocytes.

---

Hydrocortisone butyrate is a potent topical corticosteroid prodrug for the treatment of inflammatory skin conditions such as atopic dermatitis and psoriasis. A 0.1% cream formulation has Class III potency. Its high lipophilicity (logP=3.8) enhances its retention in the stratum corneum. Clinical studies have demonstrated superior efficacy compared to hydrocortisone butyrate, with comparable safety profiles. [1]

C28H40O7

488.613

488.277

C, 68.83; H, 8.25; O, 22.92

72590-77-3

72590-77-3 (probutate);57524-89-7 (valerate);508-99-6 (cypionate);125-04-2 (sodium succinate); 2203-97-6 (hemisuccinate anhydrous); 13609-67-1 (butyrate); 50-03-3 (Acetate); 74050-20-7 (aceponate); 50-23-7;

636398

White to off-white solid powder

1.2g/cm3

608.9ºC at 760 mmHg

122ºC

194.7ºC

1.547

4.093

1

7

9

35

938

7

CCC(OCC(C1(CCC2C3CCC4=CC(CCC4(C)C3C(CC12C)O)=O)OC(CCC)=O)=O)=O

FOGXJPFPZOHSQS-AYVLZSQQSA-N

InChI=1S/C28H40O7/c1-5-7-24(33)35-28(22(31)16-34-23(32)6-2)13-11-20-19-9-8-17-14-18(29)10-12-26(17,3)25(19)21(30)15-27(20,28)4/h14,19-21,25,30H,5-13,15-16H2,1-4H3/t19-,20-,21-,25+,26-,27-,28-/m0/s1

[(8S,9S,10R,11S,13S,14S,17R)-11-hydroxy-10,13-dimethyl-3-oxo-17-(2-propanoyloxyacetyl)-2,6,7,8,9,11,12,14,15,16-decahydro-1H-cyclopenta[a]phenanthren-17-yl] butanoate

Hydrocortisone buteprate; Hydrocortisone probutate; 72590-77-3; Hydrocortisone butyrate propionate; Hydrocortisone 17-butyrate 21-propionate; TS 408; Hydrocortisone probutat; DTXSID3048603;

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 : ~250 mg/mL (~511.66 mM)

Solubility in Formulation 1: ≥ 2.08 mg/mL (4.26 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 20.8 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.

---

Solubility in Formulation 2: ≥ 2.08 mg/mL (4.26 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 20.8 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.

---

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