Roles of hydrophobicity, protein binding and the probenecid-sensitive transport system in the cerebrospinal fluid delivery of nucleoside analogues with anti-viral activity

Ten nucleoside analogues with anti-herpes or anti-HIV activity were in inve stigated for their transport into the cerebrospinal fluid (CSF) following i ntravenous administration in rats. The novel anti-herpes agent 1-beta-D-ara binofuranosyl-2-thio-5-fluorocytosine (5F-araSC) showed the highest CSF/pla sma concentration ratio (>20%), while that of acyclovir (ACV) was very low (<5%), A linear relationship was observed between the partition coefficient (chloroform/water) and CSF/unbound plasma concentration in 6 of 9 agents, The exceptions were DDI, AZT and ACV, which showed much lower concentration s in the CSF than expected from their hydrophobicity and protein binding ac tivities. The effects of probenecid treatment on the CSF and plasma concent rations were measured with continuous intravenous administration of ACV, AZ T, araC and 5F-araSC, Probenecid markedly increased the CSF concentrations of ACV and AZT, although the effect was minimal in araC and 5F-araSC, These results may provide useful information for molecular design of nucleoside analogues with better transport to the brain.