Third-generation model for corticosteroid pharmacodynamics: roles of glucocorticoid receptor mRNA and tyrosine aminotransferase mRNA in rat liver

J Pharmacokinet Biopharm. 1995 Apr;23(2):163-81. doi: 10.1007/BF02354270.


A third-generation pharmacokinetic/pharmacodynamic model was proposed for receptor/gene-mediated corticosteroid effects. The roles of the messenger RNA (mRNA) for the glucocorticoid receptor (GR) in hepatic GR down-regulation and the mRNA for hepatic tyrosine aminotransferase (TAT) induction by methylprednisolone (MPL) were examined. Male adrenalectomized Wistar rats received 50 mg/kg MPL iv. Blood and liver samples were collected at various time points for a period of 18 hr. Plasma concentrations of MPL, free hepatic cytosolic GR densities, GR mRNA, TAT mRNA, and TAT activities in liver were determined. Plasma MPL profile was biexponential with a terminal t1/2 of 0.57 hr. Free hepatic GR density rapidly disappeared from cytoplasm after the MPL dose and then slowly returned to about 60% of starting level after 16 hr. Meanwhile, GR mRNA level fell to 45% of baseline within 2 hr postdosing, and remained at that level for at least 18 hr. The GR down-regulation of GR mRNA and protein turnover rate were modeled. The TAT mRNA began to increase at about 2 hr, reached a maximum at about 5 hr, and declined to baseline by 14 hr. TAT induction followed a similar pattern, except the induction was delayed about 0.5 hr. Pharmacodynamic parameters were obtained by fitting seven differential equations in a piecewise fashion. The cascade of corticosteroid steps were modeled by a series of inductions for steroid-receptor-DNA complex, two intermediate transit compartments, TAT mRNA, and TAT activity. Results indicate that GR mRNA and TAT mRNA are major controlling factors for the receptor/gene-mediated effects of corticosteroids.

Publication types

  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Adrenal Cortex Hormones / pharmacokinetics*
  • Adrenalectomy
  • Animals
  • Blotting, Northern
  • Glucocorticoids / pharmacokinetics
  • Kinetics
  • Liver / enzymology
  • Liver / metabolism*
  • Male
  • Methylprednisolone / pharmacokinetics
  • Models, Biological
  • RNA, Messenger / biosynthesis*
  • Rats
  • Rats, Wistar
  • Receptors, Glucocorticoid / biosynthesis*
  • Tyrosine Transaminase / biosynthesis*


  • Adrenal Cortex Hormones
  • Glucocorticoids
  • RNA, Messenger
  • Receptors, Glucocorticoid
  • Tyrosine Transaminase
  • Methylprednisolone