The long-term objectives of this proposal are to define the pharmacokinetics of GHB and its precursors, including their nonlinear (i.e., dose- and concentration-dependent) characteristics, and to examine how these properties may affect their renal clearance, brain distribution and effects, and gene regulation during tolerance and withdrawal. The goal of this work, therefore, is to delineate the relationships between GHB/precursor dose and blood/urine concentrations, the clearance rate of these compounds at particular concentrations (toxicokinetics), and the relationships between blood/brain concentrations and the relevant toxic effects (toxicodynamics). We submit that basic knowledge about these aspects of GHB pharmacology, obtained through animal models, is critical for the rational management of GHB toxicity and abuse.
Three specific aims are proposed.
The first aim will characterize the toxicokinetics, renal clearance and renal transport of GHB/precursors. Although the urinary excretion of GHB has been reported to be minor (less than 10 percent) in animals and in humans, GHB overdoses have been associated with extremely high urinary concentrations of GHB and its precursors. We hypothesize that GHB renal clearance may be governed in part by saturable re-absorption, possibly mediated by monocarboxylate anion transporters.
Aim 1 will therefore examine the pharmacokinetics and mechanisms of GHB/precursor clearance, and will test the hypothesis that GHB renal clearance may be affected by urinary pH and presence of transport inhibitors. The effect of gender on GHB pharmacokinetics will also be examined.
Specific aim number 2 will examine the toxicokinetics and brain toxicodynamics of GHB/precursors under single and chronic dosing conditions. We shall test the hypothesis that the dissimilar pharmacokinetic and physicochemical properties between GHB and its precursors will result in significantly different brain toxicokinetics and subsequent differences in neurochemical and membrane biophysical effects. The presence of brain transporters that may mediate GHB transport across the blood-brain barrier will also be examined.
Specific aim number 3 will examine how various factors may affect the regulation of gene expression in the brain that are induced by GHB and its precursors, particularly during tolerance development and withdrawal. Multiple biochemical pathways are associated with GHB action, and we therefore hypothesize that GHB/precursor exposure causes a myriad of changes in gene regulation, which will be monitored by the contemporary technique of micro gene-array determination. A pharmacogenetic mapping of the pharmacological effects of GHB will be obtained. The effects of tolerance development, withdrawal, gender, receptor blockade on these effects will be examined.
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