ROLE OF BRAIN-TISSUE LOCALIZED PURINE METABOLIZING ENZYMES IN THE CENTRAL-NERVOUS-SYSTEM DELIVERY OF ANTI-HIV AGENTS 2'-BETA-FLUORO-2',3'-DIDEOXYINOSINE AND 2'-BETA-FLUORO-2',3'-DIDEOXYADENOSINE IN RATS

Purpose. This study examines the central nervous system (CNS) delivery of 2'-beta-fluoro-2',3'-dideoxyadenosine (F-ddA) and 2'-beta-fluoro-2 ',3'-dideoxyinosine (F-ddI), acid stable analogues of dideoxyadenosine (ddA) and dideoxyinosine (ddI) having reduced susceptibility to purin e salvage pathway enzymes important in the metabolism of ddA and ddI, adenosine deaminase (ADA) and purine nucleoside phosphorylase (PNP), r espectively. Their CNS delivery compared to that for ddI provides insi ght into the role of brain tissue ADA and PNP in these processes. Meth ods. Brain and cerebrospinal fluid (CSF) concentration-time profiles w ere obtained for F-ddI during and after intravenous infusions of F-ddI , and for both F-ddA and F-ddI after F-ddA infusions in normal rats or rats pre-treated with the ADA inhibitor 2'-deoxycoformycin (DCF). Rat e constants for CNS entry, efflux and metabolism were estimated by com puter fits using plasma concentration-time profiles as the driving for ce functions. Results. The CNS delivery of F-ddI did not differ signif icantly from that for ddI. F-ddA, which is more lipophilic than F-ddI, provided higher brain (approximate to 8x) and CSF (approximate to 11x ) concentrations of total dideoxynucleoside (F-ddA and F-ddr) compared to F-ddI. Deamination by brain tissue ADA to form F-ddI reduced CNS l evels of intact F-ddA but provided higher brain parenchyma (5X) and CS F/plasma (3X) ratios of F-ddI relative to F-ddI controls. Thus, F-ddA functions in part as a CNS-activated prodrug of F-ddI. DCF pre-treatme nt inhibited brain tissue ADA, abolishing the prodrug effect, and enha ncing F-ddA concentrations in both brain parenchyma (5X) and CSF (6X). Conclusions. PNP metabolism does not appear to play a role in the low CNS delivery of ddI. On the other hand, deamination of F-ddA by brain tissue ADA is an important process, such that F-ddA functions in part as a CNS-activated prodrug of F-ddI. Enhanced CNS uptake of intact F- ddA can be achieved with ADA inhibition.