Methylprednisolone

Methylprednisolone is a synthetic glucocorticoid and a methyl derivative of prednisolone. Methylprednisolone is a potent anti-inflammatory agent with the capacity to profoundly inhibit the immune system.

Methylprednisolone is a corticosteroid with an anti-inflammatory activity at least five times that of hydrocortisone. An enhanced separation of glucocorticoid and mineralocorticoid effect results in a reduced incidence of sodium and water retention.

Glucocorticoids act primarily by binding to and activating intracellular glucocorticoid receptors. Activated glucocorticoid receptors bind to promoter regions of DNA (which may activate or suppress transcription) and activate transcription factors resulting in inactivation of genes through de-acetylation of histones.

Following corticosteroid administration there is a delay of several hours for the clinical effects resulting from changes in gene expression to be seen.

Other effects not related to gene expression may be more immediate.

Corticosteroids influence the kidney and fluid and electrolyte balance, lipid, protein, and carbohydrate metabolism, skeletal muscle, the cardiovascular system, the immune system, the nervous system, and the endocrine system. Corticosteroids are also critical in the maintenance of function during stress.

Methylprednisolone pharmacokinetics is linear, independent of route of administration.

Absorption

Methylprednisolone is rapidly absorbed and the maximum plasma methylprednisolone concentration is achieved around 1.5 to 2.3 hours across doses following oral administration in normal healthy adults. The absolute bioavailability of methylprednisolone in normal healthy subjects is generally high (82% to 89%) following oral administration.

Distribution

Methylprednisolone is widely distributed into the tissues, crosses the blood-brain barrier, and is secreted in breast milk. Its apparent volume of distribution is approximately 1.4 L/kg.

The plasma protein binding of methylprednisolone in humans is approximately 77%.

Metabolism

Corticosteroids are metabolised mainly in the liver but also in the kidney and are excreted in the urine.

In humans, methylprednisolone is metabolized in the liver to inactive metabolites; the major ones are 20α-hydroxymethylprednisolone and 20β-hydroxymethylprednisolone.

Metabolism in the liver occurs primarily via the CYP3A4 enzyme.

Methylprednisolone, like many CYP3A4 substrates, may also be a substrate for the ATP-binding cassette (ABC) transport protein p-glycoprotein, influencing tissue distribution and interactions with other medicines.

Elimination

The mean elimination half-life for total methylprednisolone is in the range of 1.8 to 5.2 hours. Total clearance is approximately 5 to 6 mL/min/kg. Mean elimination half-life ranges from 2.4 to 3.5 hours in normal healthy adults and appears to be independent of the route of administration.

Total body clearance following intravenous or intramuscular injection of methylprednisolone to healthy adult volunteers is approximately 15-16 L/hour. Peak methylprednisolone plasma levels of 33.67 micrograms/100 ml were achieved in 2 hours after a single 40 mg I.M. injection to 22 adult male volunteers.

Based on conventional studies of safety pharmacology and repeated dose toxicity, no unexpected hazards were identified. The toxicities seen in repeated-dose studies were those expected to occur with continued exposure to exogenous adrenocortical steroids.

Mutagenic potential

Methylprednisolone has not been formally evaluated for genotoxicity. Studies using structurally related analogues of methylprednisolone showed no evidence of a potential for genetic and chromosome mutations in limited studies in bacteria and mammalian cells.

Carcinogenic potential

Methylprednisolone has not been formally evaluated in rodent carcinogenicity studies. Variable results have been obtained with other glucocorticoids tested for carcinogenicity in mice and rats. However, published data indicate that several related glucocorticoids including budesonide, prednisolone, and triamcinolone acetonide can increase the incidence of hepatocellular adenomas and carcinomas after oral administration in drinking water to male rats. These tumorigenic effects occurred at doses which were less than the typical clinical doses on a mg/m² basis. The clinical relevance of these findings is unknown.

Reproductive toxicity

Methylprednisolone has not been evaluated in animal fertility studies. Adverse effects on fertility in male rats administered corticosterone were observed and were reversible. Decreased weights and microscopic changes in prostate and seminal vesicles were observed. The numbers of implantations and live foetuses were reduced and these effects were not present following mating at the end of the recovery period.

An increased frequency of cleft palate was observed among the offspring of mice treated during pregnancy with methylprednisolone in doses similar to those typically used for oral therapy in humans.

An increased frequency of cardiovascular defects and decreased body weight were observed among the offspring of pregnant rats treated with methylprednisolone in a dose that was similar to that used for oral therapy in humans but was toxic to the mothers. In contrast, no teratogenic effect was noted in rats with doses <1-18 times those typically used or oral therapy in humans in another study. High frequencies of foetal death and a variety of central nervous system and skeletal anomalies were reported in the offspring of pregnant rabbits treated with methylprednisolone in doses less than those used in humans. The relevance of these findings to the risk of malformations in human infants born to mothers treated with methylprednisolone in pregnancy is unknown. Safety margins for the reported teratogenic effects are unknown.