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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.
Methylprednisolone sodium succinate has the same metabolic and anti-inflammatory actions as methylprednisolone. When given parenterally and in equimolar quantities, the two compounds are equivalent in biologic activity. The relative potency of methylprednisolone sodium succinate and hydrocortisone sodium succinate, as indicated by depression of eosinophil count, following intravenous administration, is at least four to one. This is in good agreement with the relative oral potency of methylprednisolone and hydrocortisone.
Methylprednisolone sodium succinate has been investigated for acute spinal cord injury in two randomized, double-blind, comparative National Acute Spinal Cord Injury Studies (NASCIS 2 and 3). The effect of high dose methylprednisolone sodium succinate given as initial bolus of 30 mg/kg by IV for 15 minutes followed 45 minutes later by a continuous infusion of 5.4 mg/kg/hour for 24 hours was significant on neurologic recovery when given to patients within 8 hours from injury (NASCIS 2) and motor recovery was higher for those patients initiated within 3 to 8 hours from injury and treated with the same regimen for 48 hours (NASCIS 3).
Pharmacokinetics: Methylprednisolone pharmacokinetics is linear, independent of route of administration.
Absorption: After a 40 mg intramuscular dose of methylprednisolone sodium succinate to fourteen healthy adult male volunteers, the average peak concentration of 454 ng/mL was achieved at 1 hour. At 12 hours, the methylprednisolone plasma concentration has declined to 31.9 ng/mL. No methylprednisolone was detected 18 hours after dosing. Based on area-under-the-time-concentration curve, an indication of total drug absorbed, intramuscular methylprednisolone sodium succinate was found to be equivalent to the same dose administered intravenously.
Results of a study demonstrated that the sodium succinate ester of methylprednisolone is rapidly and extensively converted to the active methylprednisolone moiety after all routes of administration. Extent of absorption of free methylprednisolone following IV and IM administrations were found to be equivalent and significantly greater than those following administration of the oral solution and oral methylprednisolone tablets. Since the extent of methylprednisolone absorbed following the IV and IM treatment was equivalent in spite of the greater amount of the hemisuccinate ester reaching the general circulation after IV administration, it appears that the ester is converted in the tissue after IM injection with subsequent absorption as free methylprednisolone.
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.
No dosing adjustments are necessary in renal failure. Methylprednisolone is hemodialyzable.
Toxicology: Preclinical Safety Data: Based on conventional studies of safety pharmacology and 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.
Carcinogenesis: 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.
Mutagenesis: 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 sulfonate did not induce unscheduled DNA synthesis in primary rat hepatocytes at 5 to 10,000 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.
