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

Abstract

Receptor/gene-mediated effects of corticosteroids on hepatic tyrosine aminotransferase (TAT) were evaluated in normal rats. A group of normal male Wistar rats were injected with 50 mg/kg methylprednisolone (MPL) intramuscularly at the nadir of their plasma corticosterone (CST) rhythm (early light cycle) and sacrificed at various time points up to 96 h post-treatment. Blood and livers were collected to measure plasma MPL, CST, hepatic glucocorticoid receptor (GR) mRNA, cytosolic GR density, TAT mRNA, and TAT activity. The pharmacokinetics of MPL showed bi-exponential disposition with two first-order absorption components from the injection site and bioavailability was 21%. Plasma CST was reduced after MPL dosing, but resumed its daily circadian pattern within 36 h. Cytosolic receptor density was significantly suppressed (90%) and returned to baseline by 72 h resuming its biphasic pattern. Hepatic GR mRNA follows a circadian pattern which was disrupted by MPL and did not return during the study. MPL caused significant down-regulation (50%) in GR mRNA which was followed by a delayed rebound phase (60-70 h). Hepatic TAT mRNA and activity showed up-regulation as a consequence of MPL, and returned to their circadian baseline within 72 and 24 h of treatment. A mechanistic receptor/gene-mediated pharmacokinetic/pharmacodynamic model was able to satisfactorily describe the complex interplay of exogenous and endogenous corticosteroid effects on hepatic GR mRNA, cytosolic free GR, TAT mRNA, and TAT activity in normal rats.

Fig. 1

Pharmacokinetic model for methylprednisolone after IV and IM administration (50 mg/kg) in normal rats

Fig. 2

Pharmacodynamic/pharmacogenomic model of receptor/gene-mediated corticosteroid effects on hepatic tyrosine aminotransferase in normal rats

Fig. 3

Plasma pharmacokinetic profile of methylprednisolone after 50 mg/kg IV (top) and IM (bottom) dosing. The symbols represent individual data from rats and the solid line represents the model (Fig. 1, Table 2) fitted lines. The dashed lines depict 95% confidence intervals of model predictions

Fig. 4

Plasma corticosterone profile in normal male Wistar rats (●: mean observed data ± SD after 50 mg/kg IM MPL, ○: controls sacrificed at 14.5 and 26.5 h circadian time, solid line shows model fittings to Eq. 9 (parameters are given in Tables 3 and 4) and the broken line depicts simulated profile of CST from the circadian rhythm study [23]. The inset represents a similar plot truncated at 15h

Fig. 5

Hepatic GR mRNA (top panel) and free cytosolic GR density (bottom panel) in normal rats after 50mg/kg IM MPL. The symbols represent the mean±SD and the solid lines depict model (Fig. 2) fitted lines. The dashed line in the top panel shows the simulated circadian rhythm of GR mRNA based on results obtained from our previous circadian rhythm study (parameters are given in Tables 4 and 5)

Fig. 6

Hepatic TAT mRNA (top panel) and TAT activity (bottom panel) dynamics after 50 mg/kg IM MPL. The symbols (▲, treated; ∆, control) represent the mean ± SD and solid or dashed lines depict model (Fig. 2) predictions based on the parameters shown in Tables 5 and 6

Fig. 7

Simulated profiles of the driving forces controlling GR and TAT regulation after 50mg/kg IM MPL based on the model given in Fig. 2 and parameters given in Tables 2–6. (A) MPL, DR and DR(N) dynamics; (B) DR(N), hepatic GR mRNA and free cytosolic GR dynamics; (C) CST, CR and CR(N) dynamics and (D) CR(N), hepatic TAT mRNA and activity dynamics