ABSTRACT
PK/PD modelling will play an increasingly important role in drug development, because it will identify key properties of a drug in vivo, allowing the characterization and prediction of the time course of drug effects under physiological and pathological conditions (intensity and duration). It has developed from a descriptive to a mechanism-based approach, taking the relevant processes on the causal path between drug administration and drug effect into account. Recent developments and insights from systems biology and systems pharmacology will provide new information on the complexities of disease associated with the identification of multiple targets for drug treatment. This will give rise to new opportunities of drug combinations, which can only be developed rationally through the appropriate application of dynamical systems-based PK/PD models.
Subject(s)
Drug Discovery , Models, Biological , Pharmacokinetics , Pharmacology , Animals , Humans , Systems BiologyABSTRACT
Lipopolysaccharide-induced changes in blood-brain barrier (BBB) permeability were investigated with a pharmacological approach in vitro. Lipopolysaccharide induced a concentration- and time-dependent (non)reversible opening of the BBB, and brain astrocytes make brain capillary endothelial cells (BCEC) resistant to this BBB disruption. De novo protein synthesis was essential for the recovery, because cycloheximide prevented the recovery process. Dexamethasone pretreated BCEC were more resistant to lipopolysaccharide, while no protective response was induced by heat shock nor by inhibition of P-glycoprotein. BBB opening was tempered by free radical inhibitors (i.e., pretreatment with N-acetyl-cysteine or uric acid combined with deferroxamine mesylate). No effects of modulators of prostanoid-, leukotriene-, or platelet-activating factor pathways were observed. Therefore, lipopolysaccharide-induced BBB opening seems to be primarily mediated by excessive free radical production.
