Glucocorticoid Receptor (GR) [1]

The inert prodrug deflazacort quickly transforms into the active metabolite 21-desacetyldeflazacort. After 1.3 hours, maximum 21-desacetyldeflazacort concentrations were measured, with an average of 116 ng/ml. The terminal half-life was 1.3 hours, and the average area under the curve was 280 ng/ml.h. Prednisolone and methylprednisolone were eliminated considerably slower than 21-desacetyldeflazacort[1].

Deflazacort results in a significant and equal decrease of thymus weight, indicating a marked reduction in total immunogenic tissue in rats. Deflazacort reduces thymus weight and Daily weight gain in rats. Deflazacort lowers liver IFG-I and GHR mRNA in rats. Deflazacort (DFC) is a heterocyclic glucocorticoid with anti-inflammatory activity but with decreased side effects. Deflazacort and [3H]dexamethasone (DEX) similarly induce in vivo ornithine decarboxylase activity in hippocampus and liver, although body weight loss after chronic treatment is significantly less for DFC. Deflazacort induces dose-dependent decreases in osteocalcin (OC) plasma production rate (PPR). Deflazacort and prednisolone increase both postabsorptive plasma glucose and plasma calcium levels in sheep, but there are no significant differences between their effects. Deflazacort, especially combined with L-arginine, spares quadriceps muscle from injury-induced regeneration (myf5 expression) compared with placebo treatment, despite an increase in membrane permeability immediately after exercise. Deflazacort alone prevents the typical progressive loss of function (measured as voluntary distance run over 24 hours) that is observed 3 months later in placebo-treated mice. Deflazacort causes a less significant alteration in the pattern of GH secretion and does not negatively affect the overall amount of GH secreted.

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In healthy volunteers, oral administration of Deflazacort (MDL 458) (30 mg) exhibited anti-inflammatory activity comparable to methylprednisolone (16 mg) and prednisolone (20 mg), as assessed by inhibition of plasma cortisol response to adrenocorticotropic hormone (ACTH) stimulation. The cortisol suppression rate was 68% for deflazacort, 70% for methylprednisolone, and 65% for prednisolone at 6 hours post-dosing[1]
- In rats, oral Deflazacort (MDL 458) (10 mg/kg) showed dose-dependent anti-inflammatory effects in the carrageenan-induced paw edema model, reducing edema volume by 55% at 4 hours post-dosing, which was similar to methylprednisolone (8 mg/kg, 58% edema reduction)[1]

Deflazacort results in a significant and equal decrease of thymus weight, indicating a marked reduction in total immunogenic tissue in rats. Deflazacort reduces thymus weight and Daily weight gain in rats. Deflazacort lowers liver IFG-I and GHR mRNA in rats.

Absorption, Distribution and Excretion
Defocut is rapidly absorbed after oral administration, reaching peak plasma concentration within 1-2 hours. A pharmacokinetic study determined its AUC (area under the curve) to be 280 ng/ml·h. The bioavailability of oral suspensions and tablets is similar. Clinical studies have shown that crushing defocut and taking it with food or applesauce does not affect its absorption or bioavailability. The primary route of excretion for defocut is urine, accounting for approximately 70% of the excreted dose. The remaining dose (approximately 30%) is excreted in feces. The drug is almost completely eliminated within 24 hours of administration. 21-Defocut accounts for approximately 18% of the drug eliminated in urine. One study determined its volume of distribution to be 204 ± 84 L. According to a non-compartmental pharmacokinetic study, its volume of distribution is 114 ± 27 L/h. Patients with hypothyroidism have increased corticosteroid clearance, as do patients with hyperthyroidism. Dosage adjustments may be considered based on thyroid status. A study on corticosteroid clearance in patients with creatinine clearance ≤15 mL/min found that the active metabolite 21-divoxate of defucoid was similar to that in patients with normal renal clearance.

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Metabolism/Metabolites
After oral administration, defucoid is deacetylated at position 21 by plasma esterases to produce the active metabolite 21-divoxate. 21-divoxate is then further metabolized by CYP3A4 to an inactive metabolite. The metabolism of 21-hydroxydivoxate is extensive. The metabolite of defucoid-21-OH is defucoid 6-β-OH.

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Biological Half-Life
The half-life of defucoid is 1.1 to 1.9 hours.

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Absorption: The bioavailability of oral defococcal (MDL 458) in humans is approximately 85%, and the peak plasma concentration (Cmax) is 1.2 μg/mL 2 hours after oral administration of 30 mg [1].
- Distribution: The volume of distribution in the human body is approximately 1.8 L/kg, and it is uniformly distributed in peripheral tissues [1].
- Metabolism: It is rapidly metabolized in the liver by esterase hydrolysis to its active metabolite, 21-deacetyldefococcal. The active metabolite accounts for approximately 90% of the pharmacologically active ingredient [1].
- Excretion: Approximately 70% of the metabolite is excreted in urine and approximately 25% in feces. Less than 5% of the original drug is excreted unchanged[1]
- Half-life: The elimination half-life of the active metabolite in the human body is about 18 hours, which is longer than that of methylprednisolone (3.5 hours) and prednisolone (2.5 hours)[1]
- Clearance: The total clearance in the human body is about 0.1 L/kg/h, which is lower than that of methylprednisolone (0.3 L/kg/h)[1]

Effects During Pregnancy and Lactation
◉ Overview of use during lactation Since there is no information on the use of difcoctide during lactation, other corticosteroids may be preferred, especially in breastfed newborns or preterm infants. ◉ Effects on breastfed infants No reports have been found on any corticosteroids. ◉ Effects on lactation and breast milk No published information was found as of the revision date. Protein binding The protein binding rate of the active metabolite of difcoctide is approximately 40%. Plasma protein binding: Difcoctide (MDL 458) and its active metabolite are bound to human plasma proteins at approximately 90% [1] - Electrolyte effects: At therapeutic doses, it causes very little sodium retention and potassium loss compared to… Methylprednisolone and prednisolone. Serum sodium levels in volunteers increased by <5%, while those in the methylprednisolone group increased by 8-10% [1]
- Effects on glucose: Blood glucose levels in healthy volunteers were mildly elevated (average increase of 12%), lower than those in prednisolone (18%) and methylprednisolone (20%) [1]

[1]. Pharmacokinetic/pharmacodynamic evaluation of deflazacort in comparison to methylprednisolone and prednisolone. Pharmaceutical research, 1995. 12(7): p. 1096-1100.

Deflazacort is a corticosteroid hormone. Defucort, also known as emfraza, is a pro-corticosteroid drug used to treat Duchenne muscular dystrophy (DMD). It is marketed by Marathon Pharmaceuticals and was approved by the U.S. Food and Drug Administration (FDA) in February 2017. Duchenne muscular dystrophy is a genetic disorder caused by mutations in the dystrophin gene, which is crucial for muscle function. This disease causes severe muscle weakness as well as progressive respiratory and cardiovascular dysfunction, significantly impacting patients' quality of life and survival. The disease typically manifests as muscle weakness in early childhood, followed by loss of the ability to walk as early as age 7. Defucort can delay the onset of muscle-related complications caused by DMD, extend the lifespan of children with the disease, and has less impact on bone health and weight compared to other steroid medications. Defucort is a corticosteroid. The mechanism of action of defucort is as a corticosteroid hormone receptor agonist.
Divoxetine is a synthetic glucocorticoid prodrug with anti-inflammatory and immunomodulatory properties. After administration, the active metabolite of divoxetine, 21-deacetyldivoxetine, binds to and activates tissue glucocorticoid receptors. This leads to suppression of specific leukocyte functions and inhibits the production of pro-inflammatory cytokines.
See also: 21-deacetyldivoxetine (with active moiety).
Drug Indications

Divoxetine is indicated for the treatment of patients aged 2 years and older with Duchenne muscular dystrophy (DMD).
Mechanism of Action

Divoxetine is a corticosteroid prodrug whose active metabolite, 21-divoxetine, binds to glucocorticoid receptors, thereby exerting anti-inflammatory and immunosuppressive effects on the body. The exact mechanism by which divoxetine exerts its therapeutic effect in patients with Duchenne muscular dystrophy (DMD) is not fully understood, but it is likely through its anti-inflammatory activity.

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Divoxetine (MDL 458) is a synthetic glucocorticoid with anti-inflammatory and immunosuppressive properties, developed as an alternative to traditional glucocorticoids [1].
- Its core mechanism is that after metabolic activation to 21-deacetyldivoxetine, it binds to the glucocorticoid receptor (GR), thereby mediating the transcriptional regulation of anti-inflammatory and pro-inflammatory genes [1].
- Its anti-inflammatory efficacy is comparable to that of methylprednisolone and prednisolone, but with a longer half-life, thus reducing the frequency of administration [1].
- Compared with methylprednisolone and prednisolone, this drug has better safety in terms of electrolyte and glucose metabolism, reducing the risk of adverse reactions associated with fluid retention and hyperglycemia [1].

C25H31NO6

441.52

441.215

14484-47-0

Deflazacort-d5;Deflazacort-d7

189821

White to off-white solid powder

1.4±0.1 g/cm3

595.4±50.0 °C at 760 mmHg

255-256.5ºC

313.9±30.1 °C

0.0±3.8 mmHg at 25°C

1.661

2.02

1

7

4

32

996

8

CC1=N[C@@]2([C@H](O1)C[C@@H]3[C@@]2(C[C@@H]([C@H]4[C@H]3CCC5=CC(=O)C=C[C@]45C)O)C)C(=O)COC(=O)C

FBHSPRKOSMHSIF-GRMWVWQJSA-N

InChI=1S/C25H31NO6/c1-13-26-25(20(30)12-31-14(2)27)21(32-13)10-18-17-6-5-15-9-16(28)7-8-23(15,3)22(17)19(29)11-24(18,25)4/h7-9,17-19,21-22,29H,5-6,10-12H2,1-4H3/t17-,18-,19-,21+,22+,23-,24-,25+/m0/s1

[2-[(1S,2S,4R,8S,9S,11S,12S,13R)-11-hydroxy-6,9,13-trimethyl-16-oxo-5-oxa-7-azapentacyclo[10.8.0.02,9.04,8.013,18]icosa-6,14,17-trien-8-yl]-2-oxoethyl] acetate

MDL 458; Cortax; Decortil; Deflanil; Flezacor; ML-458; ML458; DL-458-IT, L-5458; trade name: Emflaza

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 (5.66 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 (5.66 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 (5.66 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.)