MICRODIALYSIS STUDIES OF THE DISTRIBUTION OF STAVUDINE INTO THE CENTRAL-NERVOUS-SYSTEM IN THE FREELY-MOVING RAT

Purpose. To study the extent and time course of distribution of stavud ine (d4T) into the central nervous system (CNS) and to investigate the transport mechanisms of antiviral nucleosides in the CNS. Methods, Mi crodialysis with on-line HPLC analysis was used to measure drug concen trations in the brain extracellular fluid (ECF) and cerebrospinal flui d (CSF) in the freely-moving rat. The in vivo recovery of d4T and zido vudine (AZT) was estimated by retrodialysis, which was validated by th e zero-net flux method. The CNS distribution of d4T was investigated d uring iv and intracerebroventricular (icy) infusion. In the subsequent studies, the effect of AZT on CNS distribution of d4T was examined. R esults, During iv infusion, d4T distributed rapidly into the CNS. Its brain ECF/plasma and CSF/plasma steady-state concentration ratios were 0.33 +/- 0.06 and 0.49 +/- 0.12, respectively (n = 15). During icy in fusion, the steady-state d4T concentrations in the brain ECF were 23-f old higher than those during iv infusion, whereas its steady-state pla sma levels were about the same for these two routes. Coadministration of AZT with d4T did not alter their respective brain distribution and systemic clearance at the concentrations examined. More importantly, t he steady-state brain ECF/plasma and CSF/plasma concentration ratios o f d4T were about 2-fold higher than those of AZT (0.15 +/- 0.04 and 0. 25 +/- 0.08) determined in the same animals. Conclusions. d4T readily crosses the blood-brain barrier (BBB) and blood-CSF barrier. An active efflux transport system in the BBB and blood-CSF barrier may be invol ved in transporting d4T out of the CNS. Direct icy administration of d 4T can be used to enhance its brain delivery. Moreover, d4T exhibits a more favorable penetration into the CNS than AZT and therefore may be useful in the treatment of AIDS dementia complex.