Glucocorticoid Receptor

The main reason methylprednisolone is utilized is because it reduces inflammation. Common applications include the short-term management of bronchial inflammation or acute bronchitis brought on by a variety of respiratory conditions, as well as arthritis treatments. Methylprednisolone is used to treat autoimmune illnesses, most notably systemic lupus erythematosus, both acutely and over the long term. Vestibular neuritis is also treated with it [1]. After six months, there was a significant improvement in motor function (neurologic change scores of 16.0 and 11.2, respectively; P = 0.03), sensation to pinprick (change scores of 11.4 and 6.6; P = 0.02), and touch (change scores, 8.9 and 4.3; P = 0.03) for the patients treated with methylprednisolone within eight hours of their injury as compared to those given a placebo. both in individuals whose injuries were first assessed as neurologically complete and in individuals who were thought to have incomplete lesions [2].

Methylprednisolone decreases RGC survival in rats with electrophysiologically diagnosed optic neuritis. Methylprednisolone decreases RGC survival by a nongenomic, calcium-dependent mechanism. Methylprednisolone-induced enhancement of RGC degeneration depends on calcium influx through voltage-gated calcium channels. Methylprednisolone treatment leads to a significant decrease in the number of ED1-positive cells in both rostral and caudal stumps. Methylprednisolone treatment results in a significant reduction in tissue loss in both cord stumps at 2, 4 and 8 week post-injury. Methylprednisolone leads to a long-term reduction of ED1-positive cells and spinal tissue loss, reduced dieback of vestibulospinal fibres, and a transient sprouting of vestibulospinal fibres near the lesion at 1 and 2 weeks post-lesion. Methylprednisolone at a dose of 30 mg/kg which has been shown to be effective in improving functional outcomes in rat SCI models, suppresses TNF-α expression and NF-kB activation. Methylprednisolone inhibition of NF-kB function is likely mediated by the induction of IkB, which traps NF-kB in inactive cytoplasmic complexes.

Human immortalized gastric epithelium GES-1 and human monocyte THP-1 were cultured in RPMI-1640 containing 10% FBS and 1% penicillin-streptomycin and incubated at 37°C in a humidified incubator at 5% CO2. THP-1 cells were induced in RPMI-1640 with 100 ng/mL phorbol 12-myristate 13-acetate (PMA) for 24 h for macrophage (M0), and then was further incubated for another 24 h with 20 ng/mL IFN-γ and 10 ng/mL lipopolysaccharide (LPS) for the activation of macrophages (M1)[3].

Absorption, Distribution and Excretion
Oral methylprednisolone has 89.9% the bioavailability of oral methylprednisolone acetate, while rectal methylprednisolone has 14.2% the bioavailability. Intravitreal methylprednisolone has a Tmax of 2.5h. Approximately 1/10 of an oral or IV dose of methylprednisolone will reach the vitreous humor. Further data regarding the absorption of methylprednisolone are not readily available.
Methylprednisolone and its metabolites have been collected in urine in humans. A study in dogs showed 25-31% elimination in urine and 44-52% elimination in feces.
The average volume of distribution of methylprednisolone is 1.38L/kg.
The average plasma clearance of methylprednisolone is 336mL/h/kg.
ORAL ABSORPTION IN SINGLE-DOSE STUDY OF 12 NORMAL MALE VOLUNTEERS. MEAN BIOAVAIL AFTER ORAL ADMIN 89.9%, INDICATING BETTER SYSTEMIC AVAIL OF ESTER THAN ALC. AVG ELIMINATION RATE CONSTANT AFTER ORAL ADMIN OF ESTER & ALC 0.290 H-1, HALF-LIFE OF 2.39 HR.
The pharmacokinetics of methylprednisolone (MP) were studied in five normal subjects following intravenous doses of 20, 40 and 80 mg methylprednisolone sodium succinate (MPSS) and an oral dose of 20 mg methylprednisolone as 4 x 5 mg tablets. Plasma concentrations of MP and MPSS were measured by both high performance thin layer (h.p.t.l.c.) and high pressure liquid chromatography (h.p.l.c.). 2. The mean values (+/- s.d.) of half-life, mean residence time (MRT), systemic clearance (CL) and volume of distribution at steady state (Vss) of MP following intravenous administration were 1.93 +/- 0.35 h, 3.50 +/- 1.01 h, 0.45 +/- 0.12 lh-1 kg-1 and 1.5 +/- 0.63 1 kg-1, respectively. There was no evidence of dose-related changes in these values. The plasma MP concentration-time curves were superimposable when normalized for dose. 3. The bioavailability of methylprednisolone from the 20 mg tablet was 0.82 +/- 0.11 (s.d.). 4. In vivo hydrolysis of MPSS was rapid with a half-life of 4.14 +/- 1.62 (s.d.) min, and was independent of dose. In contrast, in vitro hydrolysis in plasma, whole blood and red blood cells was slow; the process continuing for more than 7 days. Sodium fluoride did not prevent the hydrolysis of MPSS.
High-dose methylprednisolone is used to treat acute spinal cord injury (ASCI). The objective of the present study was to determine the pharmacokinetics of the pro-drug methylprednisolone hemisuccinate and methylprednisolone in accident victims with ASCI. The patients (n = 26) were treated with a bolus intravenous loading dose of 30 mg/kg MPHS within 2 hr after injury and this was followed by a maintenance infusion of 5.4 mg/kg/h up to 24 hr. Blood, CSF and saliva samples were collected up to 48 hr after the initial dose and the samples were analyzed by HPLC. Concentration-time data of MPHS and methylprednisolone were analyzed using population pharmacokinetic analysis with NONMEM software. RESULTS: Methylprednisolone hemisuccinate and methylprednisolone could be monitored in plasma and CSF. Methylprednisolone but not methylprednisolone hemisuccinate was present in saliva. High variability was seen in the methylprednisolone hemisuccinate levels in CSF. The pharmacokinetics of the pro-drug and the metabolite were adequately described by a 2-compartment model with exponential distribution models assigned to the interindividual and the residual variability. At steady state, the average measured methylprednisolone concentration in plasma was 12.3+/-7.0 microg/ml and 1.74+/-0.85 microg/ml in CSF. The CSF levels of methylprednisolone could be modeled as a part of the peripheral compartment. This study demonstrated that CSF concentrations of methylprednisolone were sufficiently high after IV. administration and reflected the concentrations of unbound drug in plasma. Salivary levels of methylprednisolone were about 32% of the plasma level and may serve as an easily accessible body fluid for drug level monitoring.
Sodium fluoride (6--8 mg/ml) inhibits hydrolysis of methylprednisolone acetate to methylprednisolone. An HPLC method for simultaneous determination of hydrocortisone, methylprednisolone and methylprednisolone acetate in plasma is presented. Analysis of plasma samples (containing NaF) for methylprednisolone acetate shows no significant change in concentration over extended periods of storage at -20 degrees C. In vitro hydrolysis of methylprednisolone acetate at 37 degrees C in human whole blood is rapid (average t1/2 = 19 min). In one cat, the bioavailabilities of methylprednisolone acetate rectally was 13% and of methylprednisolone (alcohol) rectally was 26%, relative to intravenous administration of methylprednisolone. In the same cat, the bioavailabilities of methylprednisolone acetate orally was 93% and of methylprednisolone was 82%, relative to intravenous administration of methylprednisolone. All samples collected after oral administration of methylprednisolone acetate to a human subject were found to contain only methylprednisolone (alcohol) indicating hydrolysis of the drug during absorption through the gastrointestinal membrane and/or in the liver. If the ester had the same half-life in blood in vivo as measured in vitro, it would have been measurable in plasma.
For more Absorption, Distribution and Excretion (Complete) data for METHYLPREDNISOLONE (7 total), please visit the HSDB record page.

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Metabolism / Metabolites
The metabolism of methylprednisolone is thought to be mostly mediated by 11beta-hydroxysteroid dehydrogenases and 20-ketosteroid reductases.
METAB OF 6ALPHA-METHYLPREDNISOLONE NA SUCCINATE IN RATS; METABOLITES; 6ALPHA-METHYLPREDNISOLONE, 6ALPHA-METHYL-11BETA,17ALPHA,20BETA- TRIHYDROXY-1,4-PREGNADIEN-3-ONE,21-OIC ACID, & 6ALPHA-METHYL-11BETA,17ALPHA,20,21-TETRAHYDROXY-1,4-PREGNADIEN-3-ONE 21-SUCCINATE.
Prednisone, prednisolone, and methylprednisolone are currently administered in association with cyclosporin A in the postoperative treatment of transplant patients. The aim of this work was to evaluate the effects of these corticosteroids on the expression of several forms of cytochromes p450, including p450 1A2, 2D6, 2E1, and 3A, and on cyclosporin A oxidase activity in human liver. For this purpose, human hepatocytes prepared from lobectomies were maintained in culture in a serum-free medium, in collagen-coated dishes, for 96-144 hr, in the absence or presence of 50-100 uM corticosteroids, rifampicin, or dexamethasone. To mimic more closely the current clinical protocol, hepatocyte cultures were also co-treated with corticosteroids and cyclosporin A or ketoconazole (a selective inhibitor of cytochromes p450 3A). Cyclosporin A oxidase activity, intracellular retention of cyclosporin A oxidized metabolites within hepatocytes, accumulation of cytochromes p450 proteins and corresponding messages, and de novo synthesis and half-lives of these cytochromes p450 were measured in parallel in these cultures. Our results, obtained from seven different hepatocyte cultures, showed that 1) dexamethasone and prednisone, but not prednisolone or methylprednisolone, were inducers of cytochrome p450 3A, at the level of protein and mRNA accumulation, as well as of cyclosporin A oxidase activity, known to be predominantly catalyzed by these cytochromes p450; 2) although corticosteroids are known to be metabolized in human liver, notably by cytochrome p450 3A, partial or total inhibition of this cytochromes p450 by cyclosporin or ketoconazole, respectively, did not affect the inducing efficiency of these molecules; 3) corticosteroids did not affect the half-life of cytochrome p450 3A or the accumulation of other forms of cytochromes p450, including 1A2, 2D6, and 2E1; 4) chronic treatment of cells with cyclosporin did not affect cytochrome p450 3A accumulation; 5) corticosteroids were all competitive inhibitors of cyclosporin A oxidase in human liver microsomes, with Ki values of 61 + or - 12, 125 + or - 25, 190 + or - 38, and 210 + or - 42 uM for dexamethasone, prednisolone, prednisone, and methylprednisolone, respectively; and 6) chronic treatment of cells with corticosteroids did not influence the excretion of oxidized metabolites of cyclosporin from the cells.

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Biological Half-Life
Methylprednisolone has a half life of 2.3h.
IV HALF-LIFE IS APPROX 80 MIN IN DOGS.
PLASMA HALF-LIFE IS 3-4 HR.
SINGLE DOSE STUDY OF 12 NORMAL MALE VOLUNTEERS. HALF-LIFE OF 2.39 HR.

Interactions
PHENYTOIN IS ... KNOWN TO INCR METABOLISM OF ... METHYLPREDNISOLONE IN HUMANS.
SYSTEMIC EFFECTS OF ADMIN CORTICOSTEROIDS /METHYLPREDNISOLONE/ ... MAY BE DIMINISHED BY LARGE DOSES OF BARBITURATES SUCH AS PHENOBARBITAL.
HYPERGLYCEMIC ACTION OF CORTISONE /METHYLPREDNISOLONE/ MAY OFFSET HYPOGLYCEMIC ACTION OF CHLORPROPAMIDE.
Methylprednisolone clearance was reduced in asthmatic patients also taking troleandomycin.
For more Interactions (Complete) data for METHYLPREDNISOLONE (25 total), please visit the HSDB record page.

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Non-Human Toxicity Values
LD50 Rat subcutaneous > 3,000 mg/kg body weight
LD50 Rat (Sprague-Dawley) oral (acute) > 2,000 mg/kg body weight

[1]. Methylprednisolone, valacyclovir, or the combination for vestibular neuritis. N Engl J Med, 2004. 351(4): p. 354-61.

[2]. A randomized, controlled trial of methylprednisolone or naloxone in the treatment of acute spinal-cord injury. Results of the Second National Acute Spinal Cord Injury Study. N Engl J Med, 1990. 322(20): p. 1405-11.

[3]. Glucocorticoids improve severe or critical COVID-19 by activating ACE2 and reducing IL-6 levels. Int J Biol Sci 2020; 16(13):2382-2391.

Therapeutic Uses
Anti-Inflammatory Agents, Steroidal; Antiemetics; Glucocorticoids, Synthetic; Glucocorticoids, Topical; Neuroprotective Agents
MEDICATION (VET): Treatment with methylprednisolone may be helpful if instituted within the first few hours of /spinal cord/ injury.
MEDICATION (VET): Glucocorticoids are usually contraindicated in animals with meningitis or meningoencephalitis with an infectious etiology; however, a high-dose, short-term course of ... methylprednisolone may control life-threatening complications such as acute cerebral edema and impending brain herniation.
MEDICATION (VET): In cats with mild to moderate inflammatory bowel disease (IBD) or relapse of clinical signs, and in those in which administration of oral medication is difficult, methylprednisolone ... may be effective as the sole treatment or as an adjunct to prednisone and metronidazole.
For more Therapeutic Uses (Complete) data for METHYLPREDNISOLONE (29 total), please visit the HSDB record page.

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Drug Warnings
/SRP: High dose/ /Methylprednisolone, when administered as a therapeutic agent, has been /associated with hallucinations. /From table/
Contraindicted in patients with systemic fungal infections. Adverse reactions include sodium and fluid retention, potassium depletion, muscle weakness, osteoporosis, peptic ulcer, thin fragile skin, development of Cushingoid state, glaucoma, cataracts, and negative nitrogen balance. May mask signs of infection and new infections may appear during use. May increase requirements for hypoglycemic agents in diabetic patients.
We describe a 61 year-old caucasian male diagnosed with rheumatoid arthritis. He was started on methylprednisolone pulses because of a severe flare of symmetric polyarthritis while he was on weekly intramuscular methotrexate and low-dose oral prednisone. After the second pulse of methylprednisolone the patient suddenly developed severe abdominal pain with free air under the right hemidiaphragm in the chest roentgenogram. The emergency surgery revealed the perforation of a colonic diverticulum. We suggest that methylprednisolone pulses should be carefully used in those patients over 50 years of age and/or people with demonstrated or suspected diverticular disease.
The immunosuppressive effects of glucocorticoids may result in activation of latent infection or exacerbation of intercurrent infections, including those caused by Candida, Mycobacterium, Toxoplasma, Strongyloides, Pneumocystis, Cryptococcus, Nocardia, or Ameba. Glucocorticoids should be used with great care in patients with known or suspected Strongyloides (threadworm) infection. In such patients, glucocorticoid-induced immunosuppression may lead to Strongyloides hyperinfection and dissemination with widespread larval migration, often accompanied by severe enterocolitis and potentially fatal gram-negative septicemia. /Corticosteroids/
For more Drug Warnings (Complete) data for METHYLPREDNISOLONE (33 total), please visit the HSDB record page.

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Pharmacodynamics
Corticosteroids bind to the glucocorticoid receptor, inhibiting pro-inflammatory signals, and promoting anti-inflammatory signals. Corticosteroids have a wide therapeutic window as patients may require doses that are multiples of what the body naturally produces. Patients taking corticosteroids should be counselled regarding the risk of hypothalamic-pituitary-adrenal axis suppression and increased susceptibility to infections.

C22H30O5

374.47

374.209

C, 70.56; H, 8.07; O, 21.36

83-43-2

Methylprednisolone acetate;53-36-1;Methylprednisolone (Standard);83-43-2;Methylprednisolone-d7;Methylprednisolone succinate;2921-57-5;Methylprednisolone-d3;Methylprednisolone-d4;Methylprednisolone-d2

6741

Crystals
White to practically white crystalline powder

1.3±0.1 g/cm3

571.8±50.0 °C at 760 mmHg

228-237°C (dec.)

313.7±26.6 °C

0.0±3.6 mmHg at 25°C

1.603

1.99

3

5

2

27

754

8

C[C@@]12[C@@](O)(C(=O)CO)CC[C@H]1[C@@H]1C[C@H](C)C3=CC(C=C[C@]3(C)[C@H]1[C@H](C2)O)=O

VHRSUDSXCMQTMA-PJHHCJLFSA-N

InChI=1S/C22H30O5/c1-12-8-14-15-5-7-22(27,18(26)11-23)21(15,3)10-17(25)19(14)20(2)6-4-13(24)9-16(12)20/h4,6,9,12,14-15,17,19,23,25,27H,5,7-8,10-11H2,1-3H3/t12-,14-,15-,17-,19+,20-,21-,22-/m0/s1

(6S,8S,9S,10R,11S,13S,14S,17R)-11,17-dihydroxy-17-(2-hydroxyacetyl)-6,10,13-trimethyl-7,8,9,11,12,14,15,16-octahydro-6H-cyclopenta[a]phenanthren-3-one

2934.99.9001

Powder      -20°C    3 years

                     4°C     2 years

In solvent   -80°C    6 months

                  -20°C    1 month

Note: This product requires protection from light (avoid light exposure) during transportation and storage.

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: ≥ 2.08 mg/mL (5.55 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.

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Solubility in Formulation 2: ≥ 2.08 mg/mL (5.55 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.

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Solubility in Formulation 3: ≥ 2.08 mg/mL (5.55 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 20.8 mg/mL clear DMSO stock solution to 900 μL of corn oil and mix evenly.

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Solubility in Formulation 4: 25 mg/mL (66.76 mM) in 50% PEG300 50% Saline (add these co-solvents sequentially from left to right, and one by one), suspension solution; with ultrasonication (<60°C).
Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH₂ O to obtain a clear solution.

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