Pharmacokinetic/pharmacodynamic modeling of selected receptor/gene mediated effects of corticosteroids
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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 5 th -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.