Pharmacokinetics of methylprednisolone after intravenous and intramuscular administration in rats

Abstract

Methylprednisolone (MPL) pharmacokinetics was examined in adrenalectomized (ADX) and normal rats to assess the feasibility of intramuscular (i.m.) dosing for use in pharmacodynamic studies. Several study phases were pursued. Parallel group studies were performed in normal and ADX rats given 50 mg/kg MPL (i.v. or i.m.) and blood samples were collected up to 6 h. Data from studies where normal rats were dosed with 50 mg/kg MPL i.m. and killed over either 6 or 96 h were combined to determine muscle site and plasma MPL concentrations. Lastly, ADX rats were dosed with 50 mg/kg MPL i.m. and killed over 18 h to assess hepatic tyrosine aminotransferase (TAT) dynamics. MPL exhibited bi-exponential kinetics after i.v. dosing with a terminal slope of 2.1 h(-1). The i.m. drug was absorbed slowly with two first-order absorption rate constants, 1.26 and 0.219 h(-1) indicating flip-flop kinetics with overall 50% bioavailability. The kinetics of MPL at the injection site exhibited slow, dual absorption rates. Although i.m. MPL showed lower bioavailability compared with other corticosteroids in rats, TAT dynamics revealed similar i.m. and i.v. response profiles. The more convenient intramuscular dosing can replace the i.v. route without causing marked differences in pharmacodynamics.

Tandem Analysis of Transcriptome and Proteome Changes after a Single Dose of Corticosteroid: A Systems Approach to Liver Function in Pharmacogenomics

“…The only major difference between the two studies is that the gene expression analysis were performed in animals that were given an intravenous dose of the drug and the proteomic measurements were performed in rats given an intramuscular injection of MPL. However, our previous studies comparing the two routes of MPL dosing indicated that, though there are some early differences in the pharmacokinetic profiles of MPL, the pharmacodynamics of an important biomarker tyrosine aminotransferase (TAT) expressed in liver were comparable (Hazra et al, 2007).…”

Modeling receptor/gene-mediated effects of corticosteroids on hepatic tyrosine aminotransferase dynamics in rats: dual regulation by endogenous and exogenous corticosteroids

“…Simultaneous analysis of plasma as well as muscle site PK of MPL in rats revealed incomplete bioavailability and a complex release pattern [24] from the injection site (flip-flop kinetics with two absorption rates) compared to humans [39,40] and even compared to other CS in rats [41]. Despite these complexities in PK via the IM route, examination of TAT dynamics revealed similar IM and IV response profiles [24]. Therefore, the more convenient IM dosing was chosen.…”

“…Rats were weighed, anesthetized with ketamine/xylazine, and sacrificed by aortic exsanguinations at 0.25, 0.5, 0.75, 1, 2, 4, 5,6,7,8,12,24,36,48,60,72,84 and 96 h (n = 3 per time point). Six rats injected with IM saline and sacrificed at 12 and 24 h (n = 3 per time point) served as controls.…”

“…The MPL concentrations after IV dosing were obtained from a pharmacokinetic study where four male Wistar rats were given MPL via jugular vein cannula [24]. Blood samples were collected at 0.25, 0.5, 1, 2, 3, 4 and 6 h.…”

The administration of high-dose methylprednisolone for 24 h reduced muscle size and increased atrophy-related gene expression in spinal cord-injured rats

“…Although absorption of MP from tissues has been reported to be delayed, this consideration does not appear to be significant. 2 The use of MP during the period immediately after SCI with the goal of improving neurological function continues to be a topic of controversy. Evidence of benefit from clinical trials 1 led to use of this intervention in many newly injured individuals with SCI.…”