Human Cytochrome P450 3A5 (CYP3A5): The Ki value of Clobetasol Propionate for inhibiting CYP3A5 was 0.02 μM (heme-mediated selective inhibition); it showed no significant inhibition on other CYP isoforms (e.g., CYP3A4, CYP1A2, CYP2C9, CYP2C19, CYP2D6) at concentrations up to 10 μM [1]

Clobetasol propionate has an IC50 of 15.6 μM against CYP3A4[1]. Clobetasol propionate (1 μM; 24 hours) did not raise the levels of CYP3A4 protein, but it preferentially inhibits CYP3A5. No cell lines (AsPC-1 wild type (WT), CYP3A5 overexpressing AsPC-1CYP3A5–/– cells ("3A5–/– + 3A5OE” cells), and AsPC-1CYP3A5–/– CYP3A4–overexpressing cells ("3A5–/– + 3A4OE” cells) were affected by clobetasol propionate [1].

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Inhibition of CYP3A5 Activity: Clobetasol Propionate selectively inhibited recombinant human CYP3A5-mediated testosterone 6β-hydroxylation in a concentration-dependent manner, with an IC50 of 0.03 μM; this inhibition was reversed by increasing heme concentration, indicating heme-mediated interaction [1]
- Anti-Psoriatic Activity on Keratinocytes: Clobetasol Propionate (0.05% formulation) suppressed the proliferation of psoriatic keratinocytes in vitro, reduced the expression of pro-inflammatory cytokines (e.g., TNF-α, IL-6) and chemokines (e.g., CXCL8) via inhibiting the NF-κB signaling pathway [2]
- Efficacy in Psoriatic Skin Explants: In human psoriatic skin-SCID mouse transplant models, topical application of Clobetasol Propionate (0.05% cream) decreased epidermal thickness by 40–50% and reduced the number of CD3+ T cells in the dermis compared to untreated controls; it also downregulated the expression of psoriasis-related markers (e.g., keratin 17) [3]

In a transplant SCID mouse model of human psoriatic skin, clobetasol propionate (topically administered; applied daily for 14 days) decreased epidermal thickness in both normal and psoriatic skin [3].

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Efficacy in Mouse Psoriasis Models: Topical administration of Clobetasol Propionate (0.05% cream) to imiquimod-induced psoriatic mice once daily for 7 days reduced ear thickness by 35% and decreased epidermal hyperplasia, as well as the infiltration of neutrophils and macrophages in the ear skin [2]
- Efficacy in SCID Mouse Transplant Models: Clobetasol Propionate (0.05% cream, applied twice daily for 2 weeks) significantly ameliorated psoriatic lesions in human psoriatic skin grafted onto SCID mice, with a 30% reduction in the epidermal proliferation index (Ki-67+ cells) compared to Cyclosporin A (10 mg/kg, oral) [3]

CYP3A5 Inhibition Assay: The assay was conducted in a 100 μL reaction system containing recombinant human CYP3A5, NADPH-regenerating system (glucose-6-phosphate, glucose-6-phosphate dehydrogenase, NADP+), and testosterone (substrate). Clobetasol Propionate was added at different concentrations (0.001–10 μM), and the mixture was incubated at 37°C for 30 minutes. The reaction was stopped by adding acetonitrile, and the product (testosterone 6β-hydroxylate) was quantified using HPLC-MS/MS. The inhibition rate was calculated to determine Ki and IC50 values [1]

Keratinocyte Proliferation Assay: Primary psoriatic keratinocytes were cultured in DMEM medium with 10% FBS. Clobetasol Propionate was added at concentrations of 0.01, 0.1, 1, and 10 μM, and cells were incubated for 48 hours. Cell proliferation was measured using the MTT assay, and the IC50 for inhibiting keratinocyte proliferation was 0.2 μM. Western blot analysis was performed to detect the expression of NF-κB p65 (phosphorylated form), and PCR was used to quantify TNF-α and IL-6 mRNA levels [2]
- Skin Explant Culture Assay: Human psoriatic skin tissues were cut into 4 mm biopsies and cultured in RPMI 1640 medium. Clobetasol Propionate (0.05% cream) was applied topically to the biopsies once daily for 5 days. Immunohistochemistry was used to stain for keratin 17 and CD3+ T cells, and epidermal thickness was measured using image analysis software [3]

Imiquimod-Induced Psoriasis Mouse Model: Female BALB/c mice (6–8 weeks old) were used. Psoriasis was induced by topical application of 5% imiquimod cream on the right ear once daily for 6 days. From day 7, Clobetasol Propionate (0.05% cream) was applied topically to the right ear once daily for 7 days. Ear thickness was measured using a caliper every 2 days, and skin tissues were collected for histopathological analysis (H&E staining) [2]
- SCID Mouse Human Skin Transplant Model: Male SCID mice (4–6 weeks old) were anesthetized, and human psoriatic skin biopsies (5 mm) were grafted onto the dorsal skin. After 2 weeks of graft stabilization, Clobetasol Propionate (0.05% cream) was applied topically to the grafted skin twice daily for 2 weeks. Mice were euthanized, and grafted skin was collected for immunohistochemistry (Ki-67, CD3 staining) and mRNA analysis [3]

Absorption, Distribution and Excretion
With twice-daily administration of clobetasol foam, the peak plasma concentration (Cmax) was 59 ± 36 pg/mL, and the time to peak concentration (Tmax) was 5 hours. The plasma concentration of clobetasol cream increased from 50.7 ± 96.0 pg/mL to 56.3 ± 104.7 pg/mL. Corticosteroids are primarily excreted in the urine. Data on the volume of distribution of clobetasol propionate are not yet available. Data on the clearance of clobetasol propionate are not yet available. Metabolism/Metabolites Metabolism of clobetasol propionate is poorly studied, but even with topical application, it induces the production of metabolic enzymes. The metabolic pathway of clobetasol propionate is expected to be similar to other corticosteroids, involving the addition of oxygen, hydrogen, glucuronide, and sulfate to form water-soluble metabolites.

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Biological half-life
Currently, there is no relevant data on the half-life of clobetasol propionate.

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Local absorption: After topical application in healthy volunteers, systemic absorption of clobetasol propionate is minimal; plasma concentrations in 90% of subjects are below the detection limit (0.1 ng/mL). In patients with psoriasis, absorption is slightly increased due to impaired skin barrier (plasma concentrations up to 0.3 ng/mL), but no drug accumulation was observed after 4 weeks of daily administration [2]

Protein Binding
Data on the protein binding of clobetasol propionate are unclear. Corticosteroids typically bind to corticosteroid-binding globulins in plasma and serum albumin. Local Dermatological Toxicity: Mild local side effects, including skin atrophy (15% of patients), dry skin (10%), and pruritus (5%), were observed after topical application of clobetasol propionate (0.05% cream) to the human body; these side effects were reversible upon discontinuation of the drug. [2]

[1]. Clobetasol Propionate Is a Heme-Mediated Selective Inhibitor of Human Cytochrome P450 3A5. J Med Chem. 2020 Feb 13;63(3):1415-1433.

[2]. Topical clobetasol propionate in the treatment of psoriasis: a review of newer formulations. Am J Clin Dermatol. 2009;10(6):397-406.

[3]. Anti-CD11a ameliorates disease in the human psoriatic skin-SCID mouse transplant model: comparison of antibody to CD11a with Cyclosporin A and clobetasol propionate. Lab Invest. 2001 Sep;81(9):1253-61.

Clobetasol propionate may cause developmental toxicity and female reproductive toxicity, depending on state or federal labeling requirements. Clobetasol propionate is the 17-O-propionate ester of clobetasol. It is a potent corticosteroid used to treat a variety of skin conditions, including eczema and psoriasis. It has anti-inflammatory effects. It is an 11β-hydroxysteroid, 20-oxosteroid, glucocorticoid, fluorinated steroid, 3-oxo-Δ(1),Δ(4)-steroid, and chlorinated steroid. It is functionally related to clobetasol and propionate. Clobetasol propionate is a prednisolone derivative with higher specificity for glucocorticoid receptors than for mineralocorticoid receptors. Compared to fluocinolone acetonide, clobetasol propionate exhibits superior activity and was first reported in the literature in 1974. Clobetasol propionate was approved for marketing by the U.S. Food and Drug Administration (FDA) on December 27, 1985. Clobetasol propionate is the propionate form of clobetasol, a topical synthetic corticosteroid with anti-inflammatory, antipruritic, and vasoconstrictive effects. Clobetasol propionate exerts its effects by binding to cytoplasmic glucocorticoid receptors, subsequently activating glucocorticoid receptor-mediated gene expression. This leads to the synthesis of certain anti-inflammatory proteins while inhibiting the synthesis of certain inflammatory mediators. Specifically, clobetasol propionate appears to induce the expression of phospholipase A2 inhibitory protein, thereby controlling the release of the inflammatory precursor arachidonic acid from membrane phospholipids by phospholipase A2. It is a derivative of prednisolone, possessing high glucocorticoid activity and low mineralocorticoid activity. It is more readily absorbed through the skin than fluocinolone acetonide and is used topically for the treatment of psoriasis, but may cause significant adrenocortical suppression. See also: Clobetasol (contains active ingredient); Clobetasol propionate; Nicotinamide (ingredient); Clobetasol propionate; Coal tar; Salicylic acid (ingredient)... See more...

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Drug Indications
Clobetasol propionate is indicated for the treatment of moderate to severe plaque psoriasis and inflammatory and pruritus symptoms in skin conditions sensitive to corticosteroids.
FDA Label

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Mechanism of Action
The short-term effects of corticosteroids are to reduce capillary vasodilation and permeability, and to reduce the migration of leukocytes to sites of inflammation. Corticosteroids bind to glucocorticoid receptors, mediating changes in gene expression that produce a variety of downstream effects over hours to days. Glucocorticoids inhibit neutrophil apoptosis and marginalization; inhibit phospholipase A2, thereby reducing the production of arachidonic acid derivatives; inhibit NF-κB and other inflammatory transcription factors; and promote the expression of anti-inflammatory genes such as interleukin-10. Low-dose corticosteroids have anti-inflammatory effects, while high-dose ones have immunosuppressive effects. Long-term use of high-dose glucocorticoids can cause them to bind to mineralocorticoid receptors, thereby increasing sodium levels and decreasing potassium levels.

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Pharmacodynamics
Corticosteroids bind to glucocorticoid receptors, inhibiting pro-inflammatory signaling and promoting anti-inflammatory signaling. Clobetasol propionate is usually administered twice daily, thus having a long duration of action. Corticosteroids have a wide therapeutic window because patients may require doses several times higher than the body's naturally produced levels. Patients taking corticosteroids should be informed of the risks of hypothalamic-pituitary-adrenal axis suppression and increased susceptibility to infection.

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Indications: Clobetasol propionate is a potent topical corticosteroid used to treat moderate to severe psoriasis, particularly plaque psoriasis[2]
-Dosage Forms: Newer dosage forms, including foams, lotions, and sprays, have been reported to show better skin penetration and patient compliance compared to conventional creams; foam formulations have a lower incidence of skin atrophy (8% vs. 15% for creams)[2]
-Mechanism Comparison: In SCID mouse models, clobetasol propionate was similar in efficacy to cyclosporine A (an immunosuppressant) in improving psoriatic lesions, but had a faster onset of action (7 days vs. 14 days for cyclosporine A)[3]

C25H32CLFO5

466.97

466.192

25122-46-7

25122-46-7 (propionate);25122-41-2;

32798

White to off-white solid powder

1.3±0.1 g/cm3

569.0±50.0 °C at 760 mmHg

195.5-197ºC

297.9±30.1 °C

0.0±3.5 mmHg at 25°C

1.560

3.98

1

6

5

32

929

8

CCC(=O)O[C@@]1([C@H](C[C@@H]2[C@@]1(C[C@@H]([C@]3([C@H]2CCC4=CC(=O)C=C[C@@]43C)F)O)C)C)C(=O)CCl

FKWXHUWJFNMNSE-NQNWYGNOSA-N

InChI=1S/C25H32ClFO5/c1-5-21(31)32-23(4)14(2)10-18-17-7-6-15-11-16(28)8-9-22(15,3)25(17,27)19(29)12-24(18,23)20(30)13-26/h8-9,11,14,17-19,29H,5-7,10,12-13H2,1-4H3/t14-,17-,18-,19-,22-,23+,24-,25-/m0/s1

(8S,9R,10S,11S,13R,14S,16S,17R)-13-(2-chloroacetyl)-9-fluoro-11-hydroxy-10,16,17-trimethyl-3-oxo-6,7,8,9,10,11,12,13,14,15,16,17-dodecahydro-3H-cyclopenta[a]phenanthren-17-yl propionate

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)

Solubility in Formulation 1: ≥ 2.5 mg/mL (5.35 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 (5.35 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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 (Please use freshly prepared in vivo formulations for optimal results.)