Depo-Medrol Mechanism of Action

PHARMACOLOGIC CATEGORY: Corticosteroid.
Pharmacology: Pharmacodynamics: Methylprednisolone is a potent anti-inflammatory steroid. It has greater anti-inflammatory potency than prednisolone and less tendency than prednisolone to induce sodium and water retention.
Pharmacokinetics: Absorption: One in-house study of eight volunteers determined the pharmacokinetics of a single 40 mg intramuscular dose of Methylprednisolone acetate (Depo-Medrol). The average of the individual peak plasma concentrations was 14.8 ± 8.6 ng/mL, the average of the individual peak times was 7.25 ± 1.04 hours, and the average area under the curve (AUC) was 1354.2 ± 424.1 ng/mL x hrs (Day 1-21).
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: 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. (For a list of drug interactions based on CYP3A4-mediated metabolism, see Interactions.)
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.
Toxicology: Preclinical Safety Data: Based on conventional studies of safety pharmacology, repeated-dose toxicity, no unexpected hazards were identified. The toxicities seen in the repeated-dose studies are those expected to occur with continued exposure to exogenous adrenocortical steroids.
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.
Mutagenic potential: Methylprednisolone has not been formally evaluated for genotoxicity. However, methylprednisolone sulfonate, which is structurally similar to methylprednisolone, was not mutagenic with or without metabolic activation in Salmonella typhimurium at 250 to 2,000 μg/plate, or in a mammalian cell gene mutation assay using Chinese hamster ovary cells at 2,000 to 10,000 μg/mL. Methylprednisolone suleptanate did not induce unscheduled DNA synthesis in primary rat hepatocytes at 5 to 1,000 μg/mL. Moreover, a review of published data indicates that prednisolone farnesylate (PNF), which is structurally similar to methylprednisolone, was not mutagenic with or without metabolic activation in Salmonella typhimurium and Escherichia coli strains at 312 to 5,000 μg/plate. In a Chinese hamster fibroblast cell line, PNF produced a slight increase in the incidence of structural chromosomal aberrations with metabolic activation at the highest concentration tested 1,500 μg/mL.
Reproductive toxicity: Corticosteroids have been shown to reduce fertility when administered to rats. Male rats were administered corticosterone at doses of 0, 10, and 25 mg/kg/day by subcutaneous injection once daily for 6 weeks and mated with untreated females. The high dose was reduced to 20 mg/kg/day after Day 15. Decreased copulatory plugs were observed, which may have been secondary to decreased accessory organ weight. The numbers of implantations and live fetuses were reduced.
Corticosteroids have been shown to be teratogenic in many species when given in doses equivalent to the human dose. In animal reproduction studies, glucocorticoids, such as methylprednisolone have been shown to increase the incidence of malformations (cleft palate, skeletal malformations), embryo-fetal lethality (e.g., increase in resorptions), and intra-uterine growth retardation.