Methylprednisolone

Absorption

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.

Toxicity

The oral LD50 in rats is >4g/kg. The intraperitoneal LD50 in mice is 2292mg/kg and in rats is 100mg/kg.
Data regarding acute overdoses of glucocorticoids are rare. Chronic high doses of glucocorticoids can lead to the development of cataract, glaucoma, hypertension, water retention, hyperlipidemia, peptic ulcer, pancreatitis, myopathy, osteoporosis, mood changes, psychosis, dermal atrophy, allergy, acne, hypertrichosis, immune suppression, decreased resistance to infection, moon face, hyperglycemia, hypocalcemia, hypophosphatemia, metabolic acidosis, growth suppression, and secondary adrenal insufficiency. Treat acute overdoses with symptomatic and supportive therapy, while chronic overdoses will require temporarily reduced dosages.

Chemical properties

White to Off-White Crystalline Powder

Originator

Medrol,Upjohn,US,1957

Background

Methylprednisolone is a prednisolone derivative glucocorticoid with higher potency than prednisone. It was first described in the literature in the late 1950s.
Methylprednisolone was granted FDA approval on 24 October 1957. In the outbreak of COVID-19, low dose methylprednisolone-based therapy was successful in treating COVID-19-associated pneumonia in one patient with long-term immunosuppression. The efficacy of methylprednisolone in novel coronavirus pneumonia is being investigated further in clinical trials.

Indications

Oral and intramuscular methylprednisolone are indicated for a number of endocrine, rheumatic, collagen, dermatologic, allergic, ophthalmic, respiratory, hematologic, neoplastic, edematous, gastrointestinal, nervous system, and other disorders. Intra-articular and soft tissue injections are indicated for short term treatment of acute gouty arthritis, acute and subactute bursitis, acute nonspecific tenosynovitis, epicondylitis, rheumatoid arthritis, and synovitis of osteoarthritis. Intralesional injections are indicated for alopecia areata, discoid lupus erythematosus, keloids, lichen planus, lichen simplex chronicus and psoriatic plaques, necrobiosis lipoidica diabeticorum, and localized hypertrophic infiltrated inflammatory lesions of granuloma annulare.

Definition

ChEBI: The 6alpha-stereoisomer of 6-methylprednisolone.

Manufacturing Process

The following process description is taken from US Patent 2,897,218. Six 100- ml portions of a medium in 250-ml Erlenmeyer flasks containing 1% glucose, 2% corn steep liquor (60% solids) and tap water was adjusted to a pH of 4.9. This medium was sterilized for 45 minutes at 15 psi pressure and inoculated with a one to two day growth of Septomyxa affinis ATCC 6737. The Erlenmeyer flasks were shaken at room temperature at about 24°C for a period of 3 days.
At the end of this period, this 600-ml volume was used as an inoculum for ten liters of the same glucose-corn steep liquor medium which in addition contained 10 ml of an antifoam (a mixture of lard oil and octadecanol). The fermentor was placed into the water bath, adjusted to 28°C, and the contents stirred (300 rpm) and aerated (0.5 liter air/10 liters beer). After 17 hours of incubation, when a good growth developed and the acidity rose to pH 6.7, 2 g of 6α-methylhydrocortisone plus 1 g of 3-ketobisnor-4-cholen-22-al, dissolved in 115 ml of dimethylformamide, was added and the incubation (conversion) carried out at the same temperature and aeration for 24 hours (final pH 7.9).
The mycelium (56 g dry weight) was filtered off and the steroidal material was extracted with methylene chloride, the methylene extracts evaporated to dryness, and the resulting residue chromatographed over a Florisil column. The column was packed with 200 g of Florisil and was developed with five 400-ml fractions each of methylene chloride, Skellysolve B-acetone mixtures of 9:1, 8:2, 7:3, 1:1, and methanol. The fraction eluted with Skellysolve Bacetone (7:3) weighed 1.545 g and on recrystallization from acetone gave, in three crops, 928 mg of product of MP 210° to 235°C. The sample prepared for analysis melted at 245° to 247°C.

brand name

Medrol (Pharmacia & Upjohn).

Therapeutic Function

Glucocorticoid

General Description

Methylprednisolone, 11β,17,21-trihydroxy-6α-methyl-1,4-pregnadiene-3,20-dione, isavailable unmodified or as ester derivatives.
Methylprednisolone acetate, USP
Methylprednisolone sodium succinate, USP.

Mechanism of action

Methylprednisolone is an analog of prednisolone that exhibits a more prolonged effect than prednisolone and cortisone; it has practically no mineralocorticosteroid activity and is better tolerated. Methylprednisolone is a synthetic glucocorticoid receptor agonist used to achieve prompt suppression of inflammation. 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 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.

Clinical Use

Adding a 6α-methyl group to prednisolone increases the glucocorticoid activity and effectively abolishes mineralocorticoid action. It has fivefold the glucocorticoid activity of hydrocortisone (prednisolone has fourfold the glucocorticoid activity) and none of its mineralocorticoid properties. It is used almost exclusively as a systemic product and is available as the free alcohol for oral administration and as various esters.

Safety Profile

Moderately toxic by intraperitoneal route. A steroid hormone. Human systemic effects include arrhythmias, blood pressure lowering, heart rate changes, increased body temperature, pulse rate increase, respiratory depression. When heated to decomposition it emits acrid smoke and irritating fumes.

in vitro

methylprednisolone (2-10 mg/kg) significantly inhibited tnf production. high doses of methylprednisolone (50 mg/kg) increased lps-induced il-10 levels. methylprednisolone (0.01-100 μg/ml) increased the biosynthesis of il-10 in lps-activated mouse peritoneal macrophages [1]. in wg patients and controls, methylprednisolone (mp) down-regulated the spontaneous and the staphylococcal enterotoxin b (seb)-induced release of chemokines from peripheral blood mononuclear cells (pbmc)[2]. treatment with 0.25 mm methylprednisolone inhibited acantholysis in skin cultures directly [3].

in vivo

methylprednisolone (30 mg/kg, i.v.) given immediately after sci reduced tnf-α expression by 55% (p<0.01) and nf-kb binding activity. methylprednisolone suppressed the post-traumatic inflammatory activity caused by tnf-alpha-nf-kb cascade[4]. intravenously administration of mp (30 mg/kg) reduced the number of ed1-positive cells by 82% in the rostral cord stump and 66% in the caudal stump. in the adult rat, mp administration shortly after spinal cord transection resulted in a long-term reduction of ed1-positive cells and spinal tissue loss, reduced dieback of vestibule spinal fibres, and a transient sprouting of vestibule spinal fibres near the lesion at 1 and 2 weeks post-lesion. mp treatment also significantly reduced the tissue loss in both cord stumps at 2, 4 and 8 week post-injury[5].

Drug interactions

Metabolism in the liver occurs primarily via the CYP3A4 enzyme to inactive metabolites, which are excreted in the urine Aldesleukin: avoid concomitant use.
Antibacterials: metabolism accelerated by rifampicin; metabolism inhibited by erythromycin and possibly clarithromycin; concentration of isoniazid possibly reduced. Anticoagulants: efficacy of coumarins and phenindione may be altered. Antiepileptics: metabolism accelerated by carbamazepine, fosphenytoin, phenobarbital, phenytoin and primidone.
Antifungals: increased risk of hypokalaemia with amphotericin - avoid; metabolism inhibited by ketoconazole and possibly itraconazole.
Antivirals: concentration possibly increased by ritonavir.
Ciclosporin: rare reports of convulsions in patients on ciclosporin and high-dose corticosteroids; levels of ciclosporin increased with high dose methylprednisolone.
Cobicistat: concentration possibly increased by cobicistat.
Diuretics: enhanced hypokalaemic effects of acetazolamide, loop diuretics and thiazide diuretics.
Vaccines: high dose corticosteroids can impair immune response to vaccines; avoid with live vaccines.

The Uses of Methylprednisolone

Methylprednisolone is a glucocorticoid which displays anti-inflammatory and antioxidant properties and attenuates apoptosis in oligodendrocytes after injury. 6α-Methyl Prednisolone is neuroprotective. It is an apoptosis inducer.

Clinical trials

In patients with acute spinal cord injury diagnosed in national acute spinal cord injury study (nascis) centres within 8 hours of injury, methylprednisolone treatment for 48 hours improved motor recovery at 6 weeks (p= 0.09) and 6 months (p= 0.07) after injury. In patients with acute spinal-cord injury, methylprednisolone (30 mg/kg) followed by infusion at 5.4 mg/kg/hour for 23 hours improved neurologic recovery. Among patients treated with methylprednisolone (30 mg/kg), mortality at 14 days was significantly increased secondary infection.

Metabolism

The metabolism of methylprednisolone is thought to be mostly mediated by 11beta-hydroxysteroid dehydrogenases and 20-ketosteroid reductases. Metabolism in the liver occurs primarily via the CYP3A4 enzyme to inactive metabolites excreted in the urine.

storage

Store at +4°C

Purification Methods

Recrystallise medrol from EtOAc. The UV has max at in 95% EtOH 243nm ( 14,875). The 21-acetoxy derivative has m 205-208o (from EtOAc), and [] D +95o ( c 1, CHCl3). [Spero et al. J Am Chem Soc 78 6213 1956; Fried et al. J Am Chem Soc 81 1235 1959; 1H NMR: Slomp & McGarvey J Am Chem Soc 81 2200 1959, Beilstein 8 IV 3498.]

References

[1] marchant a, amraoui z, gueydan c, et al. methylprednisolone differentially regulates il‐10 and tumour necrosis factor (tnf) production during murine endotoxaemia[j]. clinical & experimental immunology, 1996, 106(1): 91-96.
[2] torheim e a, yndestad a, bjerkeli v, et al. increased expression of chemokines in patients with wegener's granulomatosis modulating effects of methylprednisolone in vitro[j]. clinical & experimental immunology, 2005, 140(2): 376-383.
[3] swanson d l, dahl m v. methylprednisolone inhibits pemphigus acantholysis in skin cultures[j]. journal of investigative dermatology, 1983, 81(3): 258-260.
[4] xu j, fan g, chen s, et al. methylprednisolone inhibition of tnf-α expression and nf-kb activation after spinal cord injury in rats[j]. molecular brain research, 1998, 59(2): 135-142.
[5] oudega m, vargas c g, weber a b, et al. [j]. european journal of neuroscience, 1999, 11(7): 2453-2464.long‐term effects of methylprednisolone following transection of adult rat spinal cord
[6] bracken m b, shepard m j, holford t r, et al. administration of methylprednisolone for 24 or 48 hours or tirilazadmesylate for 48 hours in the treatment of acute spinal cord injury: results of the third national acute spinal cord injury randomized controlled trial[j]. jama, 1997, 277(20): 1597-1604.
[7] bracken m b, shepard m j, collins w f, et al. 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[j]. new england journal of medicine, 1990, 322(20): 1405-1411.