Methylprednisolone Chemical Properties

Melting point:

228-237°C (dec.)

alpha 

D20 +83° (dioxane)

Boiling point:

423.47°C (rough estimate)

Density 

1.0868 (rough estimate)

refractive index 

82 ° (C=1, Dioxane)

storage temp. 

0-6°C

solubility 

chloroform/methanol (9:1): 50 mg/mL, clear, faintly yellow

pka

12.46±0.70(Predicted)

form 

Solid

color 

White to Off-White

Water Solubility 

0.12g/L(25 ºC)

Merck 

14,6111

BRN 

2340300

BCS Class

2 or 4?

InChIKey

VHRSUDSXCMQTMA-PJHHCJLFSA-N

CAS DataBase Reference

83-43-2(CAS DataBase Reference)

NIST Chemistry Reference

1,4-Pregnadiene-3,20-dione, 11beta,17alpha,21-trihydroxy-6alpha-methyl-(83-43-2)

EPA Substance Registry System

Pregna-1,4-diene-3,20-dione, 11,17,21-trihydroxy-6-methyl-, (6.alpha.,11.beta.)- (83-43-2)

Safety Information

Hazard Codes 

Xi

Risk Statements 

36/37/38

Safety Statements 

22-36-26

WGK Germany 

2

RTECS 

TU4146000

F 

8-10-23

HS Code 

2937290000

Hazardous Substances Data

83-43-2(Hazardous Substances Data)

MSDS

• Language:English Provider:SigmaAldrich

Methylprednisolone Usage And Synthesis

Chemical Properties

White to Off-White Crystalline Powder

Originator

Medrol,Upjohn,US,1957

Uses

A glucocorticoid which displays anti-inflamatory and antioxidant properties and attenuates apoptosis in oligodendrocytes after injury. 6α-Methyl Prednisolone is neuroprotective.

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.

Biological Activity

methylprednisolone is a synthetic glucocorticoid receptor agonist, used to achieve prompt suppression of inflammation.cllinical trials: in patients with acute spinal cord injury diagnosed in national acute spinal cord injury study (nascis) centers 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[6]. 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 increasedsecondary infection[7]. methylprednisolone has entered

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.

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.

Synthesis

Methylprednisolone, 11|?,17|á,21-trihydroxy-6|á-methylpregna-1, 4-dien-3,20-dione (27.1.38), differs from prednisolone in the presence of a methyl group at position C6 of the steroid skeleton of the molecule. This seemingly simple difference in structure requires a different approach to synthesis. It is synthesized from hydrocortisone (27.1.8), the carbonyl group of which initially undergoes ketalization by ethylene glycol in the presence of traces of acid, during which the double bond at position C4¨C C5 is shifted to position C5¨C C6, giving the diethyleneketal 27.1.34. The product is oxidized to an epoxide (27.1.35) using perbenzoic acid. Next, the resulting epoxide is reacted with methylmagnesium bromide, and subsequent removal of the ketal protection by hydrogen reduction gives the 5-hydroxy-6-methyl derivative of dihydrocortisone 27.1.36. The resulting |?-hydroxyketone is dehydrated using an alkaline, and then the resulting 6|á-methylcortisone (27.1.37) undergoes microbiological dehydration at position C1¨CC2, giving the desired methylprednisolone (27.1.38).

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.

Metabolism

Metabolism in the liver occurs primarily via the CYP3A4 enzyme to inactive metabolites, which are 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.

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