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Vol. 288, Issue 2, 720-728, February 1999
Department of Pharmaceutics, Muscle wasting and excessive fat deposition are side effects attendant
to chronic corticosteroid treatment. Corticosteroid immunosuppression
is necessary in circumstances such as transplantation. Pharmacokinetic/pharmacodynamic (PK/PD) modeling was used to help elucidate the relationships between the events in the molecular cascade
that result in muscle wasting and fat deposition by corticosteroids. Specifically, the relationships for receptor/gene-mediated effects that
result in increased glutamine synthetase (GS) activity in skeletal
muscle were quantitatively analyzed after an i.v. bolus dose of 50 mg/kg methylprednisolone in male adrenalectomized Wistar rats. Profiles
of methylprednisolone pharmacokinetics, glucocorticoid receptor
density, and its mRNA, GS mRNA, and GS activity in gastrocnemius muscles were determined. The results were used to develop PK/PD models
using differential equations in the ADAPT II program. Two indirect
response models were tested for the dynamics of glucocorticoid receptor
mRNA regulation by activated steroid/receptor complex. Both reduction
in message synthesis and message destabilization may be involved but
with some tissue specificity. The recovery of active receptor after
down-regulation is biphasic. The initial recovery may involve receptor
recycling from the nucleus, whereas the later phase may involve de novo
synthesis of new receptor protein. The nuclear events and GS mRNA/GS
induction in rat skeletal muscle show sequential relationships for each
component for corticosteroid actions. The PK/PD models provide
mechanism-based methods of quantifying complex processes in
receptor/gene-mediated enzyme induction featuring the characteristics
of time delay and possible nonlinearity in intact tissues.
0022-3565/99/2882-0720$03.00/0
THE JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS
Copyright © 1999 by The American Society for Pharmacology and Experimental Therapeutics
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