LEADER 00000nam  2200325   4500 
001    AAI3244230 
005    20071221114353.5 
008    071221s2007                        eng d 
020    9780542998140 
035    (UMI)AAI3244230 
040    UMI|cUMI 
100 1  Hazra-Raybon, Anasuya 
245 10 Pharmacokinetic/pharmacodynamic modeling of selected 
       receptor/gene mediated effects of corticosteroids 
300    390 p 
500    Source: Dissertation Abstracts International, Volume: 67-
       11, Section: B, page: 6332 
500    Adviser: William J. Jusko 
502    Thesis (Ph.D.)--State University of New York at Buffalo, 
       2007 
520    The receptor/gene mediated effects of corticosteroids (CS)
       on various metabolic pathways were studied using 
       pharmacokinetic/pharmacodynamic (PK/PD) modeling. A 
       modified model for glucocorticoid receptor (GR) dynamics 
       in adrenalectomized (ADX) rats was proposed by integrating
       available in vitro and in vivo literature data on GR 
       dynamics, which was then applied to characterize the 
       effects of acute and chronic CS on the greater urea cycle 
       genes. To examine the feasibility of replacing ADX rats 
       with intact rats to investigate CS metabolic effects, a 
       circadian rhythm study was performed. This study, besides 
       confirming daily variation in endogenous corticosterone 
       (CST), also determined daily fluctuations in several CS 
       biomarkers related to gluconeogenesis and lipid metabolism,
       e.g., hepatic GR, tyrosine aminotransferase (TAT) dynamics,
       low-density lipoprotein receptor (LDLR) and various plasma
       lipid levels, total cholesterol (TC), LDL-cholesterol 
       (LDLC), high-density lipoprotein cholesterol (HDLC) and 
       triglycerides (TG). A quantitative structure property 
       relationship (QSPR)-PD model was developed to integrate 
       the effects of different CS in ADX rats with the circadian
       rhythm of CST in intact rats in controlling the expression
       of a hepatic TAT. The PK of 50 mg/kg of MPL after IM 
       dosing in rats showed approximately 50% bioavailability 
       and complex absorption characteristics which was described
       by two different first-order absorption pathways. The GR 
       and TAT regulation by MPL in normal rats showed more 
       complexity compared to ADX rats. An integrated PK/PD model
       incorporating components from the 5th-generation and the 
       QSPR-PD model successfully captured the complex interplay 
       of the endogenous and exogenous CS in regulating both 
       hepatic GR and TAT dynamics. Lastly, to initiate an effort
       to examine one of the major metabolic side effects of CS, 
       premature risks of atherosclerosis, the effects of MPL on 
       hepatic LDLR dynamics and plasma lipids were determined. 
       The down-regulation of LDLR mRNA by MPL was hypothesized 
       to cause an increase in plasma cholesterols. A 
       comprehensive PK/PD model, based upon this hypothesis, 
       characterized the lipid as well as LDLR mRNA dynamics. 
       Overall, this dissertation broadened our knowledge on 
       receptor/gene mediated PK/PD of CS in a more clinically 
       relevant animal model and provided a foundation for 
       further exploration of CS mediated adverse effects on 
       lipid metabolism 
590    School code: 0656 
590    DDC 
650  4 Health Sciences, Pharmacology 
650  4 Health Sciences, Pharmacy 
690    0419 
690    0572 
710 20 State University of New York at Buffalo 
773 0  |tDissertation Abstracts International|g67-11B 
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