Patients with AIDS often demonstrate central nervous system dysfunction, characterized by cognitive, motor and behavioral deficits. Evidence implicates direct brain infection by HIV as the likely cause of these neurological symptoms, referred to as AIDS dementia complex. Recent studies showing direct HIV brain infection provide a clear rationale for the importance of antiviral drugs in treating the AIDS dementia complex. It has been shown that AZT can penetrate into CSF in AIDS patients, although it is not known if the drug gains access to brain parenchyma. The existence of transport systems for the elimination of organic acids and bases from the brain and the CSF has been well documented. The anionic and cationic transport systems in the central nervous system are analogous to those in renal tubules, and can be competitively inhibited by a variety of organic acids or bases which are substrates for the same transport system. Probenecid is known to inhibit the transport of a number of substrates in the kidney and in the CNS. A recent study showed a three-fold decrease in clearance in human volunteers receiving AZT before and during probenecid treatment. Although the findings suggest probenecid may inhibit glucuronidation of AZT, the data also indicate that the ,renal excretion of AZT may be impaired by probenecid. Our preliminary findings in the rabbit demonstrate that the renal secretion of AZT is inhibited by coadministration of probenecid. perhaps by competitive inhibition. Because of the similarities in the structural specificity of the CNS and renal transport systems. and since these systems appear to be inhibited by common cosubstrates, it is reasonable to suggest that probenecid and other known transport inhibitors may alter the distribution of AZT between the CNS and plasma. This proposal will examine the effect of probenecid and salicylic acid on the renal secretion of AZT and on the distribution of AZT into CSF and brain tissue in the rabbit. The renal clearance studies will utilize constant rate infusion of AZT during a control period and a treatment period when inhibitor is coinfused. Additional experiments will be performed in ureter- cannulated animals to characterize renal clearance of AZT as a function of plasma concentration of inhibitor. Experiments will focus on the time course and extent of distribution of AZT into the CSF and brain tissue. These studies will utilize an in vivo microdialysis brain perfusion system in unanesthetized rabbits. Similar studies will examine the effect of probenecid and salicylic acid on this distributional transport.
