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.

Figure 1

Pharmacokinetic model for methylprednisolone; the symbols are described in the text and Table 3

Figure 2

Pharmacokinetic profiles of methylprednisolone (50 mg/kg) after i.v. (top panel) and i.m. (bottom panel) administration in ADX and normal rats. Symbols depict mean observed data (four rats) ± SD

Figure 3

Pharmacokinetic profiles of MPL after i.v. (top panel) and i.m. (bottom panel) administration. Symbols depict the observed data, solid lines represent the mean predictions, and the dashed lines reflect the 95% CI of the predictions

Figure 4

Pharmacokinetic profile of MPL in the injection site after 50 mg/kg dosing of MPL in normal rats. Symbols depict individual observed data from rats, solid line represents the mean predictions, and the dashed lines reflect the 95% CI of the predictions

Figure 5

Simulated (based on model in Figure 1) pharmacokinetic profiles of MPL after i.v. (● Study 1-normal, Δ Study 1-ADX, □ data from Sun et al. [19]) and i.m. (Δ Study 1-normal, ▲ Study 1-ADX, ■ Study 2, ● Study 4) administration. Symbols depict the observed data ± SD, solid lines represent the mean prediction and the dashed lines reflect the 95% CI of 51 the predictions

Figure 6

Pharmacodynamics of tyrosine aminotransferase mRNA (top panel) and activity (bottom panel) in ADX rats after i.v. or i.m. administration of 50 mg/kg MPL. Symbols depict the observed data ± SD