Linked Life Data

9918581

Source:http://linkedlifedata.com/resource/pubmed/id/9918581

Statements in which the resource exists as a subject.
PredicateObject
rdf:type
lifeskim:mentions
pubmed:issue
2
pubmed:dateCreated
1999-2-22
pubmed:abstractText
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.
pubmed:grant
pubmed:language
eng
pubmed:journal
pubmed:citationSubset
IM
pubmed:chemical
pubmed:status
MEDLINE
pubmed:month
Feb
pubmed:issn
0022-3565
pubmed:author
pubmed:issnType
Print
pubmed:volume
288
pubmed:owner
NLM
pubmed:authorsComplete
Y
pubmed:pagination
720-8
pubmed:dateRevised
2007-11-14
pubmed:meshHeading
pubmed:year
1999
pubmed:articleTitle
Pharmacokinetic/Pharmacodynamic models for corticosteroid receptor down-regulation and glutamine synthetase induction in rat skeletal muscle by a Receptor/Gene-mediated mechanism.
pubmed:affiliation
Department of Pharmaceutics, School of Pharmacy, State University of New York at Buffalo, 14260, USA.
pubmed:publicationType
Journal Article, Research Support, U.S. Gov't, P.H.S.