The composition of the cerebrospinal fluid (CSF) and brain are closely regulated by mechanisms in the central nervous system (CNS) that tend to accumulate substances necessary for the brains proper functioning as vitamins, nucleosides, deoxynucleosides and pyrimidine and purine bases, and to exclude many unnecessary substances as water-soluble drugs. However, a few water-soluble drugs (e.g., theophylline) tend to enter the CNS and cause unwanted CNS side effects. The object of the proposed studies are: 1) to gain further information about the development and function of these transport mechanisms in healthy animals as well as those who have experimentally induced diseases as uremia and liver failure; 2) to gain insight into the biochemical mechanisms underlying these transport processes; 3) to manipulate these transport mechanisms to the diseased animals (and ultimately the patient's advantage). In the proposed studies, we will focus on uridine, inosine, uracil and hypoxanthine pharmacokinetics in the CNS which will be studied intensively. The drugs theophylline and allopurinol will also be studied. Finally, the pharmacokinetics and metabolism of pantothenic acid (a vital component of Co-A) will be studied in CNS. To achieve these goals, the transport of radiolabeled drugs, pantothenic acid and nucleosides and bases into and out of the CSF, choroid plexus and brain in vivo and into the choroid plexus and brain slices in vitro in both normal animals as well as those with uremia and hepatic failure will be documented under various conditions. We will also study the ability of certain drugs and nucleoside analogues to inhibit the transfer of natural occuring nucleosides across the """"""""blood-CSF"""""""" or """"""""blood-brain"""""""" barrier. These studies have significance on multiple levels. First, they should contribute new knowledge about the role of the blood-brain and blood-CSF barriers in transporting substances into and out of the CSF; second, they will document alterations in transport in CSF and brain in models of disease; third, the information about transport may yield new functional information and, finally, these studies have important implications for therapy.
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