Detail The effect of brain injury and the acute-phase response on the pharmacokinetics and metabolism of endogenous and exogenous substrates Bibliografi Author: Rockich, Kevin Thomas ; Blouin, Robert A. (Advisor) Topik: HEALTH SCIENCES; PHARMACOLOGY Bahasa: (EN )    ISBN: 0-599-60046-2     Penerbit: University of Kentucky Press     Tahun Terbit: 1999     Jenis: Theses - Dissertation Fulltext: 9957050.pdf (0.0B; 1 download) Abstract Several inflammatory stimuli including traumatic brain injury (TBI) and endotoxin or lipopolysaccharide (LPS) activate the acute-phase response (APR) which can alter the pharmacokinetics of certain xenobiotics and the expression of P450 enzymes. It is the purpose of this research to evaluate the alterations in the pharmacokinetics and isoform-specific P450-mediated drug metabolism of a few selected substrates following TBI and the APR. In TBI patients, a certain peptide hormone, insulin-like growth factor-1 (IGF-1), is depressed. IGF-1 is secreted by several cell types and has both anabolic and mitogenic actions. The purpose of this study was to characterize the IGF-1 concentration vs. time profile following administration of rhIGF-1 and rhGH to TBI patients. The addition of rhGH to rhIGF-1 infusion allows the IGF-1 to achieve supraphysiological levels and maintain this throughout the dosing period unlike what is observed with IGF-1 alone. The second study examined the effect of LPS administration on the pharmacokinetics of chlorzoxazone (CZN), a CYP2E1 probe, in male Sprague-Dawley rats. CZN systemic clearance (Cls) and intrinsic clearance decreased by 35% and 71% in LPS treated rats, respectively. This study demonstrated that LPS administration produced reductions in the in vivo intrinsic clearance of CZN and these changes were highly correlated with in vitro activity studies. The third study examined the effect of LPS administration on CYP3A4 expression in healthy males. The Midazolam Cls was not altered following LPS administration. However, LPS caused a 19% decrease in the erythromycin breath test and a 66% decrease in the urinary 6β- hydroxycortisol/cortisol ratio. It appears that LPS administration to humans causes varied responses among the probe drugs used to measure the alterations in CYP3A4 expression. In conclusion, the addition of rhGH to a continuous infusion of rhIGF-1 caused the IGF-1 levels to reach a maximum and maintain this throughout the study period. This is probably the result of a change in the binding of IGF-1 in the systemic circulation. The final two studies showed that there is a lack of agreement of the effect of the APR on the expression of P450 between the animal and human model of sepsis. Opini Anda Klik untuk menuliskan opini Anda tentang koleksi ini! Lihat Sejarah Pengadaan  Konversi Metadata   Kembali

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