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Titolo:
Fourth-generation model for corticosteroid pharmacodynamics: A model for methylprednisolone effects on receptor/gene-mediated glucocorticoid receptordown-regulation and tyrosine aminotransferase induction in rat liver
Autore:
Sun, YN; DuBois, DC; Almon, RR; Jusko, WJ;
Indirizzi:
SUNY Buffalo, Sch Pharm, Dept Pharmaceut, Buffalo, NY 14260 USA SUNY Buffalo Buffalo NY USA 14260 Dept Pharmaceut, Buffalo, NY 14260 USA SUNY Buffalo, Dept Biol Sci, Buffalo, NY 14260 USA SUNY Buffalo Buffalo NY USA 14260 o, Dept Biol Sci, Buffalo, NY 14260 USA
Titolo Testata:
JOURNAL OF PHARMACOKINETICS AND BIOPHARMACEUTICS
fascicolo: 3, volume: 26, anno: 1998,
pagine: 289 - 317
SICI:
0090-466X(199806)26:3<289:FMFCPA>2.0.ZU;2-4
Fonte:
ISI
Lingua:
ENG
Soggetto:
MESSENGER-RNA STABILITY; PLASMA-PROTEIN BINDING; PREDNISOLONE PHARMACODYNAMICS; RIBONUCLEIC-ACID; EXPRESSION; PHARMACOKINETICS; TRAFFICKING; CELLS; IMMUNOSUPPRESSION; PHOSPHORYLATION;
Keywords:
methylprednisolone; pharmacokinetics; pharmacodynamics; indirect response models; glucocorticoid receptor; tyrosine aminotransferase; Northern hybridization; mRNA; down-regulation; receptor recycling;
Tipo documento:
Article
Natura:
Periodico
Settore Disciplinare:
Life Sciences
Citazioni:
60
Recensione:
Indirizzi per estratti:
Indirizzo: Jusko, WJ SUNY Buffalo, Sch Pharm, Dept Pharmaceut, Buffalo, NY 14260 USA SUNY Buffalo Buffalo NY USA 14260 maceut, Buffalo, NY 14260 USA
Citazione:
Y.N. Sun et al., "Fourth-generation model for corticosteroid pharmacodynamics: A model for methylprednisolone effects on receptor/gene-mediated glucocorticoid receptordown-regulation and tyrosine aminotransferase induction in rat liver", J PHAR BIOP, 26(3), 1998, pp. 289-317

Abstract

A fourth-generation pharmacokinetic/pharmacodynamic (PK/PD) model for receptor/gene-mediated effects of corticosteroids was developed. Male adrenalectomized Wistar rats received a 50 mg/kg iv bolus dose of methylprednisolone(MPL). Plasma concentrations of MPL, hepatic glucocorticoid receptor (GR) messenger RNA (mRNA) and GR density tyrosine aminotransferase (TAT) mRNA, and TAT activity in liver were determined at various rime points up to 72 hrafter MPL dosing. Down-regulation of GR mRNA and GR density were observed:GR mRNA level declined to 45-50% of the baseline in 8-10 hr, and slowly returned to predose level in about 3 days; GR density fell to 0 soon after dosing and returned to the baseline in two phases. The first phase, occurringin the first 10 hr, entailed recovery from 0 to 30%. The second phase was parallel to the GR mRNA recovery phase. Two indirect response models were applied for GR mRNA dynamics regulated by activated steroid-receptor complexA full PK/PD model for GR mRNA/GR dawn-regulation was proposed, including GR recycling theory. TAT mRNA began to increase at about 1.5 AT, reached the maximum at about 5.5 hr, and declined to the baseline at about 14 hr after MPL dosing. TAT induction followed a similar pattern with a delay of about 1-2 hr. A transcription compartment was applied as one of the cascade events leading to TAT mRNA and TAT induction. Pharmacodynamic parameters were obtained by fitting seven differential equations piecewise using the maximum likelihood method in the ADAPT II program. This model can describe GR down-regulation and the precursor/product relationship between TAT mRNA and TAT in receptor/gene-mediated corticosteroid effects.

ASDD Area Sistemi Dipartimentali e Documentali, Università di Bologna, Catalogo delle riviste ed altri periodici
Documento generato il 30/03/20 alle ore 00:50:28