Abstract
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.
Footnotes
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Send reprint requests to: Richard R. Almon, Ph.D., 107 Hochstetter Hall, Department of Biological Sciences, State University of New York at Buffalo, Buffalo, New York 14260. E-mail:almon{at}acsu.buffalo.edu
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↵1 This work was supported by Grants GM24211 and AG10629 from the National Institute of General Medical Sciences and the National Institute on Aging, National Institutes of Health.
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↵2 Present address: National Institute of Environmental Health Science, Research Triangle Park, NC 27709.
- Abbreviations:
- PK
- pharmacokinetic
- PD
- pharmacodynamic
- GS
- glutamine synthetase
- GR
- glucocorticoid receptor
- TAT
- tyrosine aminotransferase
- MPL
- methylprednisolone
- GRE
- glucocorticoid responsive element
- AIC
- Akaike information criterion
- SC
- Schwartz criterion
- ECV
- estimator criterion value
- TC
- transcription compartment
- SDRSS
- standardized residual sum-of-squares
- AUC
- area under the curve
- CL
- clearance
- Vc
- volume of distribution in the central compartment
- Vss
- volume of distribution at the steady state
- Received May 8, 1998.
- Accepted August 21, 1998.
- The American Society for Pharmacology and Experimental Therapeutics
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