Pharmacokinetic/pharmacodynamic models for corticosteroid receptor down-regulation and glutamine synthetase induction in rat skeletal muscle by a receptor/gene-mediated mechanism

Muscle wasting and excessive fat deposition are side effects attendant to c hronic corticosteroid treatment. Corticosteroid immunosuppression is necess ary in circumstances such as transplantation. Pharmacokinetic/pharmacodynam ic (PWPD) modeling was used to help elucidate the relationships between the events in the molecular cascade that result in muscle wasting and fat depo sition by corticosteroids. Specifically, the relationships for receptor/gen e-mediated effects that result in increased glutamine synthetase (GS) activ ity in skeletal muscle were quantitatively analyzed after an i.v. bolus dos e of 50 mg/kg methylprednisolone in male adrenalectomized Wistar rats. Prof iles of methylprednisolone pharmacokinetics, glucocorticoid receptor densit y, and its mRNA, GS mRNA, and GS activity in gastrocnemius muscles were det ermined. The results were used to develop PWPD models using differential eq uations in the ADAPT II program. Two indirect response models were tested f or the dynamics of glucocorticoid receptor mRNA regulation by activated ste roid/receptor complex. Both reduction in message synthesis and message dest abilization 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 ma y 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 PWPD models provide mech anism-based methods of quantifying complex processes in receptor/gene-media ted enzyme induction featuring the characteristics of time delay and possib le nonlinearity in intact tissues.