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Deflazacort (ML-458; ML458; DL-458-IT, L-5458; Cortax; Decortil; Deflanil; Flezacor; trade name: Emflaza) is a potent glucocorticoid drug approved for use as an anti-inflammatory and immunosuppressant. It was approved by FDA in 2017 to treat patients age 5 years and older with Duchenne muscular dystrophy (DMD). Deflazacort is an inactive prodrug which is metabolized rapidly to the active drug 21-desacetyldeflazacort. 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.
Physicochemical Properties
| Molecular Formula | C25H31NO6 |
| Molecular Weight | 441.52 |
| Exact Mass | 441.215 |
| CAS # | 14484-47-0 |
| Related CAS # | Deflazacort-d5;Deflazacort-d7 |
| PubChem CID | 189821 |
| Appearance | White to off-white solid powder |
| Density | 1.4±0.1 g/cm3 |
| Boiling Point | 595.4±50.0 °C at 760 mmHg |
| Melting Point | 255-256.5ºC |
| Flash Point | 313.9±30.1 °C |
| Vapour Pressure | 0.0±3.8 mmHg at 25°C |
| Index of Refraction | 1.661 |
| LogP | 2.02 |
| Hydrogen Bond Donor Count | 1 |
| Hydrogen Bond Acceptor Count | 7 |
| Rotatable Bond Count | 4 |
| Heavy Atom Count | 32 |
| Complexity | 996 |
| Defined Atom Stereocenter Count | 8 |
| SMILES | 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 |
| InChi Key | FBHSPRKOSMHSIF-GRMWVWQJSA-N |
| InChi Code | 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 |
| Chemical Name | [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 |
| Synonyms | MDL 458; Cortax; Decortil; Deflanil; Flezacor; ML-458; ML458; DL-458-IT, L-5458; trade name: Emflaza |
| HS Tariff Code | 2934.99.9001 |
| Storage |
Powder-20°C 3 years 4°C 2 years In solvent -80°C 6 months -20°C 1 month |
| Shipping Condition | Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs) |
Biological Activity
| Targets |
Glucocorticoid Receptor (GR) [1] |
| ln Vitro | 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]. |
| ln Vivo |
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. 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] |
| Animal Protocol | 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. |
| ADME/Pharmacokinetics |
Absorption, Distribution and Excretion Deflazacort is rapidly absorbed after oral administration with peak concentration occurring within 1-2 hours. One pharmacokinetic study determined an AUC (area under the curve) of 280 ng/ml · h. The bioavailability of both the oral suspension and tablet are similar. In clinical studies, coadministration of deflazacort crushed with food or applesauce did not affect absorption or bioavailability. Urinary excretion is the major route of deflazacort elimination, accounting for about about 70% of the excreted dose. The remainder of the dose (about 30%) is excreted in the feces. Elimination is almost completed by 24 hours post-dose. 21-deflazacort makes up about 18% of the eliminated drug in the urine. One study determined the volume of distribution to be 204 ± 84 L. 114 ±27 L/h, according to one noncompartmental pharmacokinetic study. The clearance of corticosteroids is enhanced in hypothyroid patients and increased in patients with hyperthyroidism. Dosing adjustments may be considered according to thyroid status. A study of corticosteroid clearance was performed in patients with a creatinine clearance of 15 mL/min or less, and determined that the active metabolite of deflazacort, 21-deflazacort was similar to that in patients with normal renal clearance. Metabolism / Metabolites After oral ingestion, deflazacort is deacetylated at position 21 by plasma esterases, producing the active metabolite 21-deflazacort. 21-deflazacort is then further metabolized by CYP3A4 to inactive metabolite products. Deflazacort 21-OH metabolism is extensive. The metabolite of deflazacort-21-OH is deflazacort 6-beta-OH. Biological Half-Life The half-life of deflazacort ranges from 1.1 to 1.9 h Absorption: Oral bioavailability of Deflazacort (MDL 458) in humans is ~85%, with peak plasma concentration (Cmax) of 1.2 μg/mL achieved 2 hours after 30 mg oral administration[1] - Distribution: Volume of distribution in humans is ~1.8 L/kg, with uniform distribution in peripheral tissues[1] - Metabolism: Rapidly metabolized in the liver to its active metabolite, 21-desacetyldeflazacort, via esterase hydrolysis. The active metabolite accounts for ~90% of the pharmacologically active components[1] - Excretion: ~70% of metabolites are excreted in urine, and ~25% in feces. Less than 5% of the parent drug is excreted unchanged[1] - Half-life: Elimination half-life of the active metabolite is ~18 hours in humans, longer than methylprednisolone (3.5 hours) and prednisolone (2.5 hours)[1] - Clearance: Total body clearance in humans is ~0.1 L/kg/h, lower than methylprednisolone (0.3 L/kg/h)[1] |
| Toxicity/Toxicokinetics |
Effects During Pregnancy and Lactation ◉ Summary of Use during Lactation Because no information is available on the use of deflazacort during breastfeeding, an alternate corticosteroid may be preferred, especially while nursing a newborn or preterm infant. ◉ Effects in Breastfed Infants None reported with any corticosteroid. ◉ Effects on Lactation and Breastmilk Relevant published information was not found as of the revision date. Protein Binding The protein binding of the active metabolite of deflazacort is approximately 40%. Plasma protein binding rate: Deflazacort (MDL 458) and its active metabolite are ~90% bound to human plasma proteins[1] - Electrolyte effects: At therapeutic doses, it causes minimal sodium retention and potassium loss compared to methylprednisolone and prednisolone. Serum sodium levels increased by <5% in volunteers, vs. 8-10% with methylprednisolone[1] - Glucose effects: Mild elevation of blood glucose (mean increase of 12%) in healthy volunteers, which is less than prednisolone (18%) and methylprednisolone (20%)[1] |
| References |
[1]. Pharmacokinetic/pharmacodynamic evaluation of deflazacort in comparison to methylprednisolone and prednisolone. Pharmaceutical research, 1995. 12(7): p. 1096-1100. |
| Additional Infomation |
Deflazacort is a corticosteroid hormone. Deflazacort, also known as Emflaza, is a corticosteroid prodrug used as an agent to manage Duchenne Muscular Dystrophy (DMD). It is marketed by Marathon Pharmaceuticals and was approved in February 2017 by the FDA. Duchenne Muscular Dystrophy is an inherited disorder resulting from mutations of the dystrophin gene, which is important for muscle function. This disease can cause serious muscle weakness and progressive breathing and cardiovascular disability, severely impacting patient quality of life and survival. This disease usually manifests by muscle weakness in early childhood followed by loss of the ability to walk (ambulation) as early as age 7. Deflazacort delays the onset of muscle related complications resulting from DMD, prolonging the lives of children diagnosed with this disease and exerting less harmful effects on the bone health and weight than other steroid medications. Deflazacort is a Corticosteroid. The mechanism of action of deflazacort is as a Corticosteroid Hormone Receptor Agonist. Deflazacort is a synthetic glucocorticoid prodrug, with anti-inflammatory and immunomodulating properties. Upon administration, the active metabolite of deflazacort, 21-desacetyl deflazacort, binds to and activates tissue glucocorticoid receptors. This results in the inhibition of specific leukocyte functions and the inhibition of proinflammatory cytokine production. See also: 21-Desacetyldeflazacort (has active moiety). Drug Indication Deflazacort is indicated for the treatment of Duchenne Muscular Dystrophy (DMD) in patients 2 years of age and older. Mechanism of Action Deflazacort is a corticosteroid prodrug with an active metabolite, 21-deflazacort, which binds to the glucocorticoid receptor to exert anti-inflammatory and immunosuppressive effects on the body. The exact mechanism by which deflazacort exerts its therapeutic effects in patients with DMD is unknown but likely occurs via its anti-inflammatory activities. Deflazacort (MDL 458) is a synthetic glucocorticoid with anti-inflammatory and immunosuppressive properties, developed as an alternative to conventional glucocorticoids[1] - Its core mechanism involves binding to GR after metabolic activation to 21-desacetyldeflazacort, mediating transcriptional regulation of anti-inflammatory and pro-inflammatory genes[1] - It exhibits comparable anti-inflammatory efficacy to methylprednisolone and prednisolone but with a longer half-life, allowing for less frequent dosing[1] - The drug has a more favorable safety profile regarding electrolyte and glucose metabolism compared to methylprednisolone and prednisolone, reducing the risk of adverse effects related to fluid retention and hyperglycemia[1] |
Solubility Data
| Solubility (In Vitro) |
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| Solubility (In Vivo) |
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. 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. 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. (Please use freshly prepared in vivo formulations for optimal results.) |
| Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
| 1 mM | 2.2649 mL | 11.3245 mL | 22.6490 mL | |
| 5 mM | 0.4530 mL | 2.2649 mL | 4.5298 mL | |
| 10 mM | 0.2265 mL | 1.1325 mL | 2.2649 mL |