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 2 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 IV administration, is at least 4-1. This is in good agreement with the relative oral potency of methylprednisolone and hydrocortisone.
Pharmacokinetics: Methylprednisolone pharmacokinetics is linear, independent of route of administration.
Absorption: After a methylprednisolone sodium succinate 40 mg IM dose to 14 healthy adult male volunteers, the average peak concentration of 454 ng/mL was achieved at 1 hr. At 12 hrs, the methylprednisolone plasma concentration has declined to 31.9 ng/mL. No methylprednisolone was detected 18 hrs after dosing. Based on area under the concentration-time curve (AUC), an indication of total drug absorbed, methylprednisolone IM sodium succinate was found to be equivalent to the same dose administered IV.
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 breastmilk. 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 (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 (t½) for total methylprednisolone is in the range of 1.8-5.2 hrs. Total clearance is approximately 5-6 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.
Carcinogenesis: Long-term studies in animals have not been performed to evaluate carcinogenic potential.
Mutagenesis: There was no evidence of a potential for genetic and chromosome mutations when tested in limited studies performed in bacterial and mammalian cells.
Reproductive Toxicity: Corticosteroids have been shown to reduce fertility when administered to rats.
Corticosteroids have been shown to be teratogenic in many species when given in doses equivalent to the human dose. In animal reproduction studies, glucocorticoids eg, methylprednisolone have been shown to induce malformations (cleft palate, skeletal malformations) and intra-uterine growth retardation.